CHNG 1: VITAMIN

i cng
Vitamin l nhm cc hp cht c phn t lng tng i nh, c tnh cht l
ha khc nhau nhng c bit cn thit cho hot ng sng ca bt k c th sinh vt
no.
Vitamin cn cho c th sng vi lng rt nh xp x 0,1-0,2g (trong khi cc
cht dinh dng khc khong 600g) v c vai tr nh cht xc tc.
Cho n nay c c 30 loi vitamin, xc nh c cu trc ha hc, kho
st v tnh cht vt l, tnh cht ha hc cng nh tc dng sinh hc ca chng.
Cch gi tn vitamin: c ba cch:
- Da vo tc dng sinh l ca vitamin thm anti vo bnh c trng thiu
vitamin.
- Da vo ch ci.
- Da vo cu trc ha hc.
Th d: vitamin C, tn ha hc: axit ascocbic, antisocbut.
Phn loi:
Cc vitamin c phn nhm trn cc c s sau:
- Kh nng ha tan
- Vai tr sinh ha
- Cu trc ha hc
Cch phn loi thng dng nht c chp nhn l phn loi theo kh nng ha
tan, c th chia vitamin lm hai nhm ln:
1. Nhm vitamin ha tan trong nc: Vitamin B1 (tiamin), Vitamin B2
(riboflavin), Vitamin B3 (axit pantotenic), Vitamin B5 (nicotinamit), Vitamin B6
(piridoxin), Vitamin B7 (biotin), Vitamin B10 (axit folic), cc vitamin B12 (cc
cianocobalamin), vitamin B15 (axit pangaminic), vitamin C, vitamin P (citrin),
vitamin U (S-metyl-metionin).
2. Nhm vitamin ha tan trong du bo: Vitamin A (antixerophtalmias), cc
vitamin D, cc vitamin E, cc vitamin K
- Cc loi vitamin tan trong nc xc tc v tham gia vo qu trnh lin quan vi
s gii phng nng lng (nh oxi ha kh, phn gii cc cht hu c) trong c
th.
- Cc loi vitamin tan trong cht bo (du) tham gia vo cc qu trnh hnh thnh
cc cht trong cc c quan v m.
* Tnh cht sinh hc ca cc nhm vitamin
Nhm cc Prostetic vitamin
Nhm cc inductive vitamin
Cc vitamin
Cc vitamin B v K
Cc vitamin A, C, D v E
Tn ti t nhin
Thng thng
Ch trong nhng loi t bo nht
nh ca c th ng vt bc cao
Vai tr ca chng Khng th thiu c trong trao Ch tham gia thc hin mt s
i cht. Ti cn thit cho s nhim v c bit. Khng phi l
sng. L phn ca coenzim
yu t khng th thiu cho s sng.
Khng ng vai tr trong s to
thnh ca coenzim.
Nng ca Rt n nh
Thay i mnh
chng trong m
-1-

Tn ti trong mu Ch yu trong cc tiu phn c

hnh dng
Kh nng tng Cc vi khun rut tng hp ra
hp trong c th
Kh nng ngn C tt c cc khng vitamin
cn hot ng tng ng
ca chng
S dng qu liu Thc t khng c s dng qu
liu

Ch yu trong huyt tng

Trong rut khng t tng hp ra
c
Khng c cc khng vitamin thch
hp
Trong mi trng hp u c th
gy ra qu liu

* Tc dng b sung ln nhau ca cc vitamin

Thng thng cc vitamin trong cng mt nhm c tc dng b sung, hon
thin, lm tng tc dng ca nhau. Cc nhm i din cng tc dng nh th ny
gm c:
- Nhm cc vitamin lm tng kh nng chng li vim nhim gm c vitamin A,
B1, B2, C, D, H, P.
- Nhm cc vitamin bo m cho h thn kinh hot ng hon ho gm vitamin A,
B1, B2, C.
- Nhm cc vitamin khi ng vic to mu gm c vitamin A, B2, B12, axit folic,
C, D.
- Nhm cc vitamin chi phi ti vic to m xng v rng gm c vitamin A, B1,
C, D.
- Nhm cc vitamin chi phi ti hot ng sinh dc gm c A, C, E.
- Nhm tr gip s tng trng: gm tt c cc vitamin tr vitamin H.
* Nhu cu cn thit ca cc vitamin
Ch k Tn
hiu cc
vitamin

Bnh
vitamin

thiu Nhu cu
hng
ngy
[mg]
Kh
mt 1,5-2,0
(xerophthalmia),
ph i gic
mc
(hyperkeratosis)

Axerophtol

Calciferol

Ci
xng 0,025
(rachitis)

Tocopherol

Cc ri lon v (20)
sinh sn

-2-

Mt n v Lng
quc t (1 gy c
NE)
0,34 mg A- Ngi
axetat
ln: 60,6 mg - 10 triu
carotin
NE
Tr em:
25-45
nghn
NE
0,025
g Hng
ergocalciferol ngy
trn
100-150
ngn NE
1mg
- tocopherolaxetat

Vitamin chng Cc ri lon v (0,1)

1 g 2-metyl- xut
huyt ng mu
1,4(antihemorragias)
naftoquinon
B1
Thiamine
Bnh t ph 1-2
3
g (beriberi)
thiamin.HCl
Bnh vim thn
kinh
(polyneuritis)
B2
Riboflavin
Vim gic mc 1,5-2
5
g (keratitis)
riboflavin
Vim
da
(dermatitis)
B3
Nicotinamide
Bnh
thiu 15-20
vitamin
PP
(pellagra)
B6
Pyridoxine
Bnh ng kinh 1-2
(epileptiform)
Bc (M)
Folic acid
Hng cu khng 1-2
l
(megaloblastis),
thiu
mu
(anemia)
B5
Pentothenic acid Triu
chng (10)
Burning Feet
B12
Cyanocobalamin Thiu mu c (0,001)
tnh (anaemiapernicious)
C
Ascorbic acid
Bnh
thiu 75
0,05 mg axit
vitamin
ascorbic
( ) = nhu cu hng ngy ch s liu c tnh
1.1. Cc loi vitamin tan trong cht bo (du)
1.1.1. Vitamin A v tin vitamin ca n (caroten):
T nm 1909, Step tm ra vai tr ca vitamin A v caroten bng cch cho
chut n thc phm ly ht cht tan trong cht bo th chut gy v cht.
Osborn, Mendel (1920), Eiler (1929) v Mur (1930) cho rng caroten l
provitamin A (tin vitamin A). Trong thc vt lng caroten ph thuc vo mu
xanh: rau mu xanh thm cha nhiu caroten hn rau mu xanh nht.
- Vitamin A c gi l cht chng li mt hay axerophtol
- Triu chng thiu vitamin A: qung g, lc tranh ti tranh sng khng nhn
thy.
- Tc dng ca cc vitamin A: bo v mt, gip c th tng trng, tng s to
mu, m bo cc hot ng v ging.
- Thiu vitamin dn n cc nguy c:
+ Chm ln v ngng pht trin.
+ Sng ha cc mng nhy ( niu o, ph nang, ng tiu ha,..) c bit l
sng ha gic mc gy m ha.
-3-

+ D b ly nhim.
Vitamin A c hai dng quan trng l vitamin A1 v A2.

OH

Vitamin A1: Retinol

OH

Vitamin A2: 3,4-dehydroretinol

Tnh cht: Vitamin A1 v A2 c th tn ti di nhiu dng ng phn hnh

hc, nhng ch c mt s dng c hot tnh sinh hc m thi. Vitamin A tham gia
vo qu trnh trao i lipit, gluxit, v mui khong. Khi thiu vitamin A dn n
cc hin tng:
- Gim s tch ly protein gan v ngng tng hp abumin huyt thanh.
- Gim lng glicogen v tng tch ly axit pivuric no, c v gan do nh
hng lm gim vitamin B1 v axit lipoic cn thit chuyn ha axit pivuric.
- Lm tng si thn v lm gim kali nhiu b phn khc nhau.
Vitamin A tham gia vo vic duy tr trng thi bnh thng ca biu m, trnh
hin tng sng ha.
Vitamin A c nhiu trong cc ng vt bin: gan c, trng, tht t vitamin A
hn. Cc loi c qu c mu da cam nh c chua, c rt c cha nhiu tin
vitamin A. Tin vitamin A l -caroten:

- Sn xut vitamin A (retinol)

Trong cng nghip, vitamin A c sn xut t hai ngun nguyn liu l gan
c bin v ha cht qua con ng tng hp ha hc.
Sn xut vitamin A t gan c bin:
Nguyn liu chnh l gan c thu, c mp, c voi,... Vit Nam ch c nh my
c hp H Long Hi Phng khai thc v sn xut du gan c bin. Hm lng
vitamin A trong du gan cc loi c rt khc nhau. Theo cc nh sn xut Php
th hm lng nh sau:
+ C thu: 600-1000 iu/g
1 IU = 0,3 microgam
retinol

-4-

+ C fletan: 25.000-60.000 iu/g

+ C thon trng: 10.000 iu/g
+ C thon , c mp: 25.000 iu/g
Cch sn xut du gan c ty thuc vo hm lng vitamin A cha trong du
cao thp khc nhau m c phng php sn xut cng khc nhau:
+ Phng php sn xut du gan c hm lng vitamin thp
C ti m ly gan, p mui hoc p .
Ra sch, thi hay xay, p ly du.
lnh 0-3oC, lc ly tm, thu ly du. Ch trnh nh sng v nhit
lnh trnh phn hy. Du gan c rt k mt s kim loi nng nh Fe hay
CH2Cl2
+ Phng php sn xut du c m c
Chit du gan c vi etanol. Ct loi cn trong chn khng.
Cn x l vi NaOh (x phng ha)
X l vi CaCl2 to mui khng tan, ly tm.
Chit cn vi axeton, bay hi, chit ete.
+ Phng php sn xut du c c c bng chng ct phn t
im si ca du gan c kh cao nn c ct chn khng c 0,05 mmHg.
Sau ct vitamin A 0,001 mmHg t 50-60oC
Sn xut vitamin A bng con ng tng hp
iu ch vitamin A-acetat i t citral qua -ionon v ahdehit 14:
+ iu ch andehit C14
H3C

H3C

CH3

H3C

CH3

CH3

CH3

CH3

CHO

axeton/H

CH3

CH3

18-8

CH3

18-9

18-20
beta-ionon

citral (geranial)
H3C

CH3

O
CH

ClCH2COOC2H5

CH

C
H

CH

CH3

18-21

CH3
H3C

CH3
CH2

CH

CHO

CH3
CH3

18-22

+ iu ch hp cht trung gian 18-26

-5-

andehit C14

COOC2H5

CH

CH3 - CO - CH=CH2

NH3 long

18-23

CH3

CH3

C)2Ca

(HC

CH

CH=CH2

CH

CH2OH

18-25

OH

CH3

CH

CH3
CH

CH2OH

BrMgC

2 C2H5MgBr

18-25

CH

CH2OMgBr

18-26

+ iu ch Vit-A-axetat
H3C

CH3
CH2

CH

CHO

18-26

H3C

CH3

CH3

CH3

C
C

CH3
CH3

CH - CH2OMgBr

OMgBr

18-22

18-27
CH3

CH3
H3C

CH3

H2O + NH4Cl

CH2

H
C

CH=C

CH - CH2OH

OH
CH3
CH3

CH3

H2, Pd/CaCO3 H3C

CH3
CH2

H
C

CH=C

CH

C
H

CH - CH2OH

OH
CH3

H3C

CH3

CH3

CH3

1)Ac2O/pyridin
OCOCH3

2) HBr
3) NaHCO3

CH3

18-4
vitamin A-acetat (retinylaxetat)

+ iu ch retinal ca Glaxo

-6-

H3C

CH3

H3C

CH

CH3
C

CH

OH

CH3COCH=CH - CH=C(CH3) - CH=CH2

CMgX

CH3

CH3

18-30

18-31
CH3

H3C

CH3
C

CH = CH - CH =C(CH3) - CH=CH2

hidro hoa rieng phan

OH

OH

CH3

18-32
CH3
H3C

CH3

H
C

C
H

OH

CH = CH - CH =C(CH3) - CH=CH2

dehidrat hoa va dong phan hoa

OH

CH3

18-33
CH3

CH3

OH

18-1
retinol

+ Sn xut cc tin vitamin A (cc caroten)

Trong thc vt thng khng tm thy vitamin A m ch c cc tin vitamin A,
cng nh trong c th ngi, bn thn t n khng th tng hp c vitamin A
nhng t tin vitamin A nhn c t cc cht dinh dng thc vt trong gan v
theo kt qu nghin cu mi nht l c trong rut cng c chuyn ha thnh
vitamin A. Ngoi tr cc ng vt n tht th do chng khng n thc n thc vt
nn nh vy lng vitamin A cn thit ch c ly t tht ng vt m n n vo.
Tin vitamin A u thuc nhm cc caroten. Cc cht mang c tnh tin
vitamin A l cc caroten cha polien, lipocrom, l nhng cht mu c th ha tan

-7-

trong m, trong cc dung mi ha tan m. i din quan trng nht ca caroten l

-caroten (18-30), -caroten (18-6), -caroten (18-31) v criptoxanten (-hidroxi-caroten) (18-32). Cc cht ny cng tn ti trong t nhin. Cng thc ch khc
nhau phn R.
H3C

CH3

CH3

CH3
R

CH3

CH3
CH3

Tn -caroten (18-30)
H3C
R

H3C

-caroten (18-6)

-caroten (18-6)

Criptoxanten (18-32)

H3C

H3C

H3C

H3C

CH3

CH3

H3C

CH3

OH

H3C

CH3

Cc loi caroten c tnh cht vt l cng tng i khc nhau, sau y l mt

s tnh cht ca chng:
-caroten
-caroten
-caroten
o
chy [ C]
187
183
152-153
max
454 , 485
450 , 476
437, 462, 494
Mu
Tinh th lng tr, Tinh th lng tr 6 Bt v nh hnh,
- tm
cnh, m
mu
Trong cu to ca tt c cc hp cht ny u c cha nhm cu trc -ionon
c trng ca vitamin A. Vic chuyn ha cc tin vitamin A thnh vitamin A
c enzim carotinase thc hin bng cch ly ln phn t nc v ct mch
thng. Nh trong cu to ca -caroten, ta thy n hon ton i xng v v mt l
thuyt, t mt phn t -caroten c th to ra 2 phn t vitamin A. Nhng kinh
nghim thc t cho thy vic ph hy phn t khng mang tnh i xng v v th
c t khong 100 phn t -caroten th bnh qun ch to ra c 40 phn t
vitamin A, cn cc tin vitamin A khc th hiu sut to ra vitamin A cn thp hn.
Ngun nguyn liu cha caroten:
+ Trong cc loi cy v qu (thc vt): c rt, du da, gc, b ng,
+ Trong rong bin
H3C

CH3

CH3

CH3
R

CH3

CH3

CH3

Tn

Echinenon (18-33)

-8-

Torularhodin (18-34)

H3C

H3C

H3C

H3C

COOH

CH3

+ Sn xut -caroten bng phng php chit sut t thc vt

T carot, sy kh, xay nh, chit vi ete, du ha hoc axeton thu c dch
chit. C chn khng thu c cn chit. Lm lnh cho kt tinh, lc, ra li vi ete
du ha lnh.
T 20kg c rt thu c 1g caroten.
+ Sn xut -caroten bng tng hp ha hc
C nhiu phng php c cng b nhng u tun theo phng php tng
hp hi t sau:
C19 + C2 + C19 = C40
C16 + C8 + C16 = C40
C18 + C4 + C18 = C40
C14 + C12 + C14 = C40
Sau y l quy trnh sn xut -caroten theo nguyn l: C19 + C2 + C19 = C40 (4
giai on)
a, Giai on tng hp andehit C16(18-37): xut pht t andehit C14

-9-

H3C

CH3

CH3

H3C

CHO

CH3

CH3

HC(OC2H5)3

CH(OC2H5)2

CH3C6H4SO3H
CH3

CH3

18-35

18-22 (andehit C14)

H3C

CH3

CH3

OC2H5

CH2=CHOC2H5

C
H

ZnCl2/toC

OC2H5
OC2H5
CH3

18-36

H3C

CH3COOH

CH

CH3

CH3

CH

CHO

CH3

18-37 (andehit C16)

b, Giai on tng hp andehit C19 (18-40)

-10-

AcONa/H2O

H3C

CH3

CH3

H3C

CH3

CH3

HC(OC2H5)3

CHO

CH(OC2H5)2

CH3

CH3

18-38

andehit C16
H3C

CH3

CH3

CH3

OC2H5

CH3CH=CHOC2H5
CH

CH3COOH/ZnCl2

OC2H5

OC2H5
CH3

18-39
H3C

CH3

CH3

CH3COOH/AcONa/H2O

CH3

CHO

CH3

18-40
andehit C19

c, Giai on tng hp 15,15, -dehidro--caroten (18-43)

-11-

H3C

CH3

CH3

CH3

CHO

+ BrMgC

CMgBr

2
18-40

CH3

andehit C19

OMgBr
H3C

H3C

HC

CH3

CH3

CH3

H3C

CH

H3C

CH3

CH3

OMgBr
CH3

18-41

OH

H3C

CH3

H3C
H3C

H2O

CH3

CH3

HC

CH3
C

CH

H3C

CH3

OH
CH3

18-42

CH3

HCl/C2H5OH

H3C
H3C

H3C

CH3

CH3

CH3

CH3

H3C

H3C

18-43

15,15 -dehidro--caroten
d, Giai on tng hp -caroten (18-6)
H3C
1, H2/Pd, CaCO3

H3C

CH3

CH3

CH3

18-43
2, Dong phan hoa
CH3

CH3

-caroten
+ Cng dng v liu dng ca -caroten

-12-

CH3

H3C

CH3

- Cng dng:
Chng kh gic mc
C tc dng ti to mt, lm tng t l hng cu
L nhn t iu tr bnh ly nhim (nhim khun)
- Liu dng: Liu dng vitamin A thng c biu din bng cc n v quc
t (IU) hay ng lng retinol (RE), vi 1 IU = 0,3 microgam retinol. Do sn
xut retinol t cc tin vitamin trong c th ngi c iu chnh bng lng
retinol c sn trong c th, nn vic chuyn ha ch p dng cht ch cho thiu ht
vitamin A trong ngi. Vic hp th cc tin vitamin cng ph thuc ln vo
lng cc lipit c tiu ha cng tin vitamin; cc lipit lm tng s hp th tin
vitamin.
Cht v mi trng ha hc ca n

Microgam retinol tng ng trn microgam

cht

Retinol

Beta-caroten, ha tan trong du

beta-caroten, thc n thng thng

1/12

alpha-caroten, thc n thng thng

1/24

Beta-cryptoxanthin, thc n thng

1/24
thng

1.1.2. Vitamin E (Tocoferol)

Ba dn xut vitamin E l: dng , , - tocoferol. Tt c vitamin E u c
nhm C16H33(-(CH2)3-CH-CH3). Cc dng ny khc nhau do s sp xp cc nhm
metyl vng benzopiran: -tocoferol khc -tocoferol v tr 7 khng cha
nhm metyl cn - tocoferol thiu nhm metyl v tr 5. Cng thc cu to ca
- tocoferol nh sau:

-13-

CH3
HO

H3C

CH3
CH3

CH3

CH3

CH3

Tocoferol cht lng khng mu, ha tan tt trong du thc vt, ru v ete.
Tocoferol kh bn vi nhit, c th chu ng nhit 1700C khi un nng trong
khng kh. Tuy nhin tia t ngoi ph hy nhanh tocoferol.
Vitamin E nh hng qu trnh sinh sn ca ng vt, gip bo m chc nng
bnh thng ca nhiu m v c quan. Vitamin E lm tng tc dng ca protein v
vitamin A, ngoi ra n cn c tc dng ngn cn cc axit bo cha no khi b oxi
ha. Khi thiu vitamin E, s to phi s b cn tr, ng thi xy ra s thoi ha c
quan sinh sn, teo c, thoi ha ty sng v suy nhc c th.
Do tnh cht chng oxy ha mnh nn trong k ngh du m, vitamin E c
dng lm cht bo v cht bo khi b oxy ha v trnh hin tng i. Ngun
nguyn liu iu ch vitamin E l mm lua m. Vitamin E c nhiu trong b, rau
x lch, du thc vt, chui.
1.1.3.Vitamin K
Vitamin K l mt trong nhng yu t tham gia vo qua trnh ng mu.
Vitamin k l nhng dn xut ca naphtoquinon, c hai loi:
- Vitamin K1 dng du vng nht, kt tinh - 200C, nhnh bn ch cha 20
nguyn t carbon.
O

CH3

CH3

CH3

CH3

CH3
O

- Vitamin K2 tinh th nng chy 520C, cu to nhnh bn cha 30-45 nguyn

t carbon.
O

CH3

CH3

CH3

CH3

n=5-8
CH3
O

Vitamin K2

Vitamin K khng tan trong nc ch tan trong cht bo v cc dung mi nh

ete, ru, benzen, axeton. B phn hy nhanh di tc dng ca tia t ngoi do cu
trc quinon b bin i, ngoi ra n cng b phn hy nhanh chng khi un nng
trong mi trng kim.
Khi thiu vitamin K thi gian ng mu s b ko di. Hot tnh ca vitamin K2
ch khong 60% vitamin K1. ngi bnh thiu vitamin t xy ra v rut c cc

-14-

vi khun c kh nng tng hp vitamin ny. Tuy nhin khi s hp th vitamin K b

c ch hoc s tng hp vitamin K gp kh khn s xut hin triu chng thiu
vitamin K.
Vitamin K c nhiu trong cc loi rau xanh, c chua, c rt, gi . ngun
ng vt vitamin K c trong gan, thn, v tht, th giu vitamin K hn tht trng.
1.1.4. Vitamin D
a, Tc dng sinh hc v ha hc ca vitamin D
Vitamin D bao gm mt s dng c cu trc gn nhau nh vitamin D1, D2, D3,
D4, D5,

Name
Vitamin D1

Chemical composition
Structure
molecular compound of
ergocalciferol
with
lumisterol, 1:1

Vitamin D2

ergocalciferol (made from

ergosterol)

Vitamin D3

cholecalciferol
(made
from 7-dehydrocholesterol
in the skin).

Vitamin D4

22-dihydroergocalciferol

Vitamin D5

sitocalciferol (made from

7-dehydrositosterol)

Tuy nhin ch 2 dng D2 v D3 l ph bin v c ngha.

Khi thiu vitamin D, tr em s dn n cc triu chng nh suy nhc c th,
chm mc rng, xng tr nn mm v cong. Bnh ci xng tr em c th xy
ra t 3-4 thng tui ko di n 1-2 tui. Hin tng ci xng cng c th gp
tui mun hn: 5-7 tui.

-15-

CH2

Vitamin D2
Ergocanxiferol

Vitamin D3
Cholecanxiferol

Ngoi ra vitamin D tham gia vo qu trnh tiu ha, trao i canxi, photpho,
lm tng hm lng photpho huyt thanh v chuyn ha phtpho dang hp
cht hu c thnh dng hp cht v c trong c th.
Trn da ngi c 7- dihidro cholesterol, l tin vitamin D, di nh sng mt
tri s chuyn thnh vitamin D. Do tm nng cng l mt bin php cha tr
tre con b ci xng.
Vitamin D dng tinh th nng chy 115-1160C, khng mu, khng tan trong
nc, ch tan trong: clorofom, benzen, axeton, v ru. Vitamin D d b phn hy
khi c mt cc cht oxi ha v axit v c.
Tr em, ph n mang thai v cho con b c nhu cu v vitamin D cao hn.
Ngun vitamin i vi ngi l gan c, m c, lng trng, sa, nm men.
nh sng t ngoi c th bin tin vitamin D thnh vitamin D bc sng
250-300m.
Cc tin vitamin D l nhng hp cht cha khung steroit 4 vng lin hp v
cc mch nhnh khc nhau. Bao gm tin vitamin D3 (18-44), tin vitamin D2 (1845), tin vitamin D4 (18-46), tin vitamin D5 (18-47) v tin vitamin D6 (18-48).
18

19

HO

-16-

CH3
H3C

18-44

CH3

R=
17

CH3

H3C

18-45

ergosterol
(pro-vitamin D2)

CH3

R=
17

(3-beta)-7-dehydro cholesterol
(pro-vitamin D3)

CH3
CH3

H3C

18-46

CH3

R=
17

22,33-dihidro-ergosterol
(pro-vitamin D4)

CH3
C2H5

H3C

18-47

R=
17

CH3

7-dehydro-sitosterol
(pro-vitamin D5)

CH3

7-dehydro-stigmasterol
(pro-vitamin D6)

CH3
C2H5

H3C

18-48

R=
17

CH3

T cc tin vitamin bng vic ct m vng B th cc vitamin D tng ng c

to thnh:
- Vitamin D3 l vitamin D t nhin bi v dehidro-cholesterol c tch tr li
di da ca ngi v cc ng vt c v. Di tc dng ca tia t ngoi th vitamin
D3 c to ra .
- Ngoi 2 tin vitamin D t nhin l 18-45, 18-46 th cn c ba tin vitamin D
nhn to cng c bit ti l 18-46, hp cht c th bt ngun t 18-44, tip na
l t sitosterol thc vt hoc stigmasterol dn n 18-47 hoc 18-48. C 5 tin vitamin
D ny u c b khung steroit (khung a vng) ging nhau, ch khc nhau phn mch
nhnh. Ergosterol l tin vitamin c duy nht mt ni i phn mch nhnh.
-17-

18-44 vitamin D2
18-45 vitamin D3
Nguyn tc chung tng hp vitamin D:
Tin vitamin D UV
vitamin D
b, Ngun nguyn liu v sn xut mt s sn phm ca vitamin D
Trong cng nghip ch yu ch sn xut hai loi l vitamin D2 v provitamin D,
cn vitamin D thin nhin c chit xut t du gan c cng vi vitamin A nh
cp trong sn xut du gan c. Ngoi ra vitamin D c trong mt s sn phm ng vt
nhng t l tng i thp.
Ngun nguyn liu ch yu sn xut vitamin D2 l ergosterol ly t nm
men (levure) hoc sinh khi sn xut penicillin.
b1. Sn xut ergosterol (provitamin D2)
- Sn xut sinh khi cha ergosterol
Trong ln men mc penicillin sn xut khng sinh, sau khi thu khng sinh
penicillin cn li khi khun ty c cha khong 15% cht kh trong hm lng
ergosterol l khong 0,5% (Nu mt phn xng sn xut penicillin c th tch thit b
ln men 500m3, mt nm c th thi ra khong 350 tn khun ty kh t c th chit
ly ra khong 1500-1900 kg ergosterol. Trong khun ty penicillin c c vitamin B1
(25-35mg/kg), vitamin B2 (10-25mg/kg).
Cng c th thu ergosterol t khun ty ln men Aspergillus niger.
Nm men cng l ngun nguyn liu chit ly ergosterol. Men lm bnh m
sau khi p c khong 0,18-0,25%, c loi n 3% ergosterol cha trong men sy kh
(nm men cn l ngun nguyn liu sn xut phc hp vitamin (B1, B2, PP, H,
PAD, axit folic,) ng thi l ngun m giu dinh dng (gn vi m ng vt)
c dng rng ri trong vic chng suy dinh dng cc cng ng thiu ngun
m, ngoi ra cn dng trong chn nui. T nhng thp k su mi ca th k XX,
nm men c sn xut nhiu trong qui m cng nghip.
- Chit ly ergosterol t sinh khi hoc nm men
Trong nm men, cc vitamin v ergosterol lin kt rt chc vi cc protein v
th mun chit xut ergosterol cn phn thy phn ph hy lin kt vi protein.
Thng vic thy phn c tin hnh bng axit hay enzim (thy phn kim t dng
v cc vitamin nhm B b ph hy). n gin nht l s dng qu trnh t phn
(autolyse): Khi 40-45oC protease c trong t bo nm men lm ph v cc lin
kt protein-vitamin, protein- ergosterol gii phng ra cc vitamin v ergosterol
trng thi t do. Sau chit ly cc vitamin B bng nc v ergosterol bng ancol.
Quy trnh sn xut thng c tin hnh nh sau:
+ Chit phc hp vitamin B: Cho nm men p kh (100kg) vo ni chu p sut
hai v, thm vo 20 lt nc v un 1100C trong vng 25-30 pht, sau cho vo
dch thy phn 80 lt cn nng t 50%. Khuy 45-50 pht nhit 75-780C
lm ng t anbumin. Lm lnh n 100C lng anbumin. Lc, phn dch lc
cha phc hp vitamin B, phn b cha ergosterol. Phn dch lc ct thu hi cn trong
p sut gim n dung dch phc hp vitamin B cha 50% cht kh, sau lm kh
thu c hn hp vitamin B. Phn b c ht kh trong chn khng n ht cn, sy
chn khng c m < 2%, y l nguyn liu chit ly ergosterol.
+ Chit phn lp ly ergosterol (18-44, provitamin D2): Cho b nm men sy
kh trn vo thit b hai v, cho vo bn phn cn, un hi lu trong 1 gi. Lc,
b chit thm 2 ln nh th. Dch cn gp li, ct chn khng thu hi cn, cn kh cn

-18-

li cha lipit (T 100kg nm men thu c khong 25 kg lipit). Cho lng lipit trn
vo dung dch NaOH 45% v un nng x phng ha. Sau lm lnh xung 00C50C kt tinh ergosterol. Lc thu c ergosterol th (trong dch lc cha mui natri
ca cc axit bo). Kt tinh li ergosterol trong hn hp dung mi cn-toluen 4:1. Sy
kh thu c ergosterol. C th tinh ch ergosterol trong cn 950 hoc trong CHCl3
hay trong ete, axeton. Sn phm ngm 1.5 H2O c chy 1660C. Ph UV c max
263, 271, 282, 293 nm. Tinh th d b nh sng chuyn thnh mu vng. Cn bo qun
lnh (<00C) v trong kh tr.
b1. Sn xut vitamin D2 (ergocalaferol, 18-49)
Nguyn tc ca s chuyn ha ca ergosterol thnh ergocalaferol v cc hp
cht khc, di tc dng ca tia t ngoi. di tc dng ca tia cc tm th bc u
precalciferol c to thnh, cht ny ngoi vic to ra sn phm mong mun c tc
dng vitamin D l ergcalciferol (vitamin D7), n cn to ra 2 hp cht c c tnh,
khng c tc dng vitamin D l lumisterol, tachysterol.
+ Qu trnh chiu x, iu ch vitamin D2
Ha tan ergosterol trong ete c nng 0,3-0,5%, cho dung dch ny i qua
ng c chiu sng bng n thch anh dng nh sng thy ngn vi bc sng cc tm
vng 275-300nm nhit si ca dung mi. Dch phn ng sau khi chiu x l cht
lng snh, ct loi dung mi n khi dung dch c nng tng ln 100 ln (lc ny
thnh phn cc cht c trong dch phn ng nh sau: ergocalaferol 55-60%, ergosterol
cn tha cha chuyn ha 10-13%, lumisterol 15-20%, tachysterol 10-12%. Lm lnh
xung 8-100C kt tinh ergosterol cha phn ng. Tinh th ergosterol to ra c
lc, dch lc c di p sut gim 50mmHg loi ht ete, thu c cn.
Cn c ha tan trong hn hp ete-metanol 1:2, sau bc hi i 50% dung
mi v kt tinh cc sterol (c lumisterol v tachysterol). Lc, dch lc c ui ht
dung mi, thu c cn dng nha ny ch yu l ergocalaferol. c th tch
c ergocalaferol (vitamin D2) sch cn phi chuyn sang dng este dinitrobenzoat
ca n.
+ To este dinitrobenzoat ca vitamin D2 (ergocalaferol dinitrobenzoat)
Cho nha (1kg) trn vo 2,5 lt piridin dng kh nit hoc CO2 vo ui
oxi, khuy cho tan sau cho vo 0,8kg 3,5-dinitrobenzoyl clorua, duy tr nhit
phn ng khng ln qu 600C. Tip tc khuy trong 4h. Sau ct chn khng
50mmHg loi bt mt na lng piridin. Tip cho hn hp trn 6,5 lt nc
nng 500C, khuy k v lng. Gn loi nc-piridin, gn v li ra cho n lc ht
piridin. Cui cng ngm v khuy cn vi 2,5 lt metanol loi axit dinitrobenzoic.
Lc loi dch metanol. Cn c ha tan trong axeton, ty mu bng than hot tnh
(1,5-2%), dch lc c lm lnh -100C qua m. Tinh th to ra c em lc, sn
phm este mu vng c chy 145-1470C (H=30%) so vi nha l
ergocalaferol dinitrobenzoat.
+ Thy phn este ergocalaferol dinitrobenzoat to ergocalaferol (vitamin D2)
Cho lng ergocalaferol dinitrobenzoat trn ha tan trong dung dch KOH
5% trong metanol sau un hi lu cho n khi mu vng bin mt v ta mu tm
xut hin. Lc nng loi ta kalidinitrobenzoat (trong lung kh nit). Dch lc c
pha long vi nc si n khi xut hin vn c khi ang nng. Sau lm lnh
xung -5 n -10oC. Tinh th to ra c lc, ra li vi nc lnh hoc cn long

-19-

10% lnh. Sy kh thu c ergocalciferol (H=75%). Sn phm tinh th mu trng c

chy 113oC-114oC, D=82,6. Nu cha t th kt tinh li trong metanol.
c, Cng dng v liu dng ca vitamin D
Vitamin D v cc dn xut c cng dng trn 3 nhm bnh
- Phng v iu tr ci xng do suy dinh dng
+ Ci xng v suy dinh dng nguyn nhn l do thiu vitamin D trong n ung
v do t ra nng. Bo thai v tr s sinh ang b nu thiu vitamin D cn phi b sung
(qua b m hoc qua sa 400iu/ngy), tt nht nn dng dng c c vitamin A ln D.
Nu tr b a chy, mt vng da th phi dng ng tim.
+ Vitamin D3 (cholecalciferol, ergocalciferol) dng chng ci xng vi liu 5005000iu/ngy, thng phi hp thm canxi. iu tr suy dinh dng, ci xng
nng hoc thiu nng ph giao cm phi dng ti liu 50.000-150.000 iu/ ngy.
- iu tr ci xng do hp th v do long xng: Bnh ci xng do hp thu c
ba dng:
+ Thiu photphat: Ri lon hp thu Ca, P khng phi l do hp thu t vitamin
nhng b sung vitamin D liu cao vi P s cait thin bnh.
+ Do gen: v thiu loi gen c hiu m 25-OH-D3 khng chuyn ha thnh 1,25(OH)2-D3, ng l phi b sung 1,25-(OH)2-D3 b vo nhng v cht ny cha c
sn phm cng nghip nn phi iu tr bng vitamin D3 vi liu 20.000200.000iu/ngy.
- iu tr thiu nng ph gip trng: c im l thiu canxi huyt v tha
photphat. Dng vitamin D liu cao 50.000-250.000 iu/ngy s ci thin s hp thu
canxi, huy ng c canxi t xng tng cng cho mu. Vitamin D c bo ch
di nhiu dng v c mi 1mg40.000iu.
1.2. Cc vitamin tan trong nc
1.2.1. Vitamin B1 (Tiamin):
Vitamin B1 l loi vitamin rng ri trong thin nhin:
CH3
N

CH3

CH2OH

NH2

Tinh th vitamin B1 tan tt trong nc. Vitamin B1 bn trong mi trng trong

axit, nhng b phn hy nhanh chng khi un nong trong mi trng kim.
Di dng tiaminpirophotphat, vitamin B1 tham gia vo h thng enzim
decacboxil-oxy ha cc xetoaxit. Khi c th thiu vitamin B1 s dn n vic tch ly
cc xetoaxit lm hn lon s trao i cht km theo cc hin tng bnh l nh gim
st s tit dch v gy bing n, t ph ngoi ra cng nh hng xu n h thn kinh.
Trung bnh mi ngi cn 1-3 mg vitamin B1 / ngy.
Trong thc phm vitamin B1 thng tn ti song song vi vitamin B2 v
vitamin PP, nht l trong phn phi ca ht ng cc.
Tuy nhin vitamin B1 thng tp trung phn c ht ng cc, v vy go cng
xay k th lng vitamin B1 cng ngho. Trong qu trnh bo qun la go vitamin B1
cng d b phn hy theo thi gian v iu kin bo qun.

-20-

Vitamin B1 nhy cm vi nhit , do vy trong qu trnh ch bin thc phm

cn phi lu vn ny. Vitamin B1 c nhiu trong nm men, cm go, gan,
thn,tim.
1.2.2 Vitamin B2 (riboflavin)
Vitamin B2 c tch t sa nm 1993. Trong cu to ca vitamin B2 c cha
hp cht riboza nn c gi l riboflavin. Vitamin B2 tahm gia vn chuy hydro
nhiu enzym, khi vitamin B2 chuyn t dng (I) sang dng (II)( khng mu).
CH2OH

CH2OH
CHOH

CHOH

CH2

CH2
H3C

NH

H3C

H3C

N
H

H
N

+2H
-2H

H3C

NH

Dng I
Dng II
Khi thiu vitamin B2 vic to nn cc enzim oxy-ha kh b ngng tr lm nh
hng n s pht trin ca c th. Vitamin B2 cn cn thit cho sinh sn t bo biu
b rut, tng sc khng ca c th, tng kh nng to mu v nh hng n s
pht trin ca bo thai.
Vitamin B2 c nhiu trong nm men bnh m, men bia, u, tht, gan, thn, tim,
trng, sa, c v ru xanh. Vitamin B2 c tng hp t t bo thc vt v vi sinh vt.
1.2.3. Vitamin B6 (piridoxal, piridoxamin, piridoxin)
Vitamin B6 c tch ra dng tinh th t nm men v cm go nm 1938.
Cu to ca vitamin B6 c cng nhn sau khi c tng hp nm 1939. Vitamin B6
c nm, men bia, gan, tht b. Khi thiu vitamin B6 s xut hin mt s bnh ngoi
da, bnh thn kinh, st cn, rng lng, tc
CH2OH
HO

H3C

CH2NH2
HO

CH2OH

H3C

CH2OH

Piridoxamin

Piridoxal

Piridoxin, tinh th khng mu, v hi ng, v ha tan tt trong ru v nc.

Cc dng vitamin B6 u bn khi un nng trong dung dch axit v kim nhng khng
bn khi c mt cht oxi ha.
1.2.4. Vitamin PP (Axit nicotinic)
Axit nicotinic c Huber tng hp t 1870 bng cch oxi ha nicontin. Nhng
n 1937 mi pht hin tnh cht vitamin ca n.

-21-

COOH

CONH2

Axit nicotinic

Amit ca axit nicotinic

Khi thiu vitamin PP s vy ra triu trng sng mng nhy rut v d dy, sau
da b sn si nht l nhng ni tip xc vi nh sng mt tri.
c th ng vt mt phn vitamin PP c th c tng hp t triptophan nh
s tham gia ca vitamin B2 v B6. V vy nu dng thc n m protein c gi tr thp
tc l c t triptophan ng thi thiu c B2 v B6 th s ko theo hin tng thiu
vitamin PP
1.2.5. Vitamin C (axit ascorbic)
Tn ti trong thin nhin di dng axit ascobic, axit dehidroascocbic v dng
lin kt ascocbigen, chnh l dng lin kt ca vitamin C vi polypeptit.
Vitamin C l mt dn xut ca dng glucoz
O

CH

CH
O

HO

H
HO

HO

HO
O

HO

CH2OH

O
H
CH2OH

Vitamin C (axit ascocbic)

Khi c th b thiu vitamin C s xut hin cc triu chng nh chy mu chn

rng, chy mu cc l chn lng hoc c quan ni tng.
Vitamin C cn lin quan n s hnh thnh cc hoocmon ca tuyn gip v
tuyn thng thn. Vitamin c rt cn thit cho c quan tng sc khng v chng
li cc hin tng chong, ng c bi ha cht cng nh c t ca vi trng.
Vitamin C c nhiu trong rau qu nh cam, chanh, du, c chua, rau ci. Trong
cc loi ng cc, trng hoc tht hu nh khng c vitamin C.

-22-

CHNG 2: CHT KHNG SINH

i cng
S pht trin v vi sinh vt hc ni chung, v vi sinh vt cng nghip ni ring,
vi bc ngoc lch s l pht minh v i v cht khng sinh ca Alexander Fleming
(1982) m ra k nguyn mi trong y hc: khai sinh ra ngnh cng ngh sn xut
cht khng sinh v ng dng thuc khng sinh vo iu tr cho con ngi.
Thut ng" cht khng sinh" ln u tin c Pasteur v Joubert (1877) s dng
m t hin tng km hm kh nng gy bnh ca vi khun Bacillus anthracis trn
ng vt nhim bnh nu tim vo cc ng vt ny mt s loi vi khun hiu kh lnh
tnh khc. Babes (1885) nu ra nh ngha hot tnh khng khun ca mt chng l
c tnh tng hp c cc hp cht ho hc c hot tnh km hm cc chng i
khng.
Nicolle (1907) l ngi u tin pht hin ra hot tnh khng khun ca Bacillus
subtilis c lin quan n qu trnh hnh thnh bo t ca loi trc khun ny. Gratia v
ng nghip (1925) tch c t nm mc mt ch phm c th s dng iu tr
hiu qu cc bnh truyn nhim trn da do cu khun.
Mc d vy, trong thc t mi ti nm 1929 thut ng " Cht khng sinh" mi c
Alexander Fleming m t mt cch y v chnh thc trong bo co chi tit v
penicillin.
Thp k 40 v 50 ca th k XX ghi nhn nhng bc tin vt bc ca ngnh
cng ngh sn xut khng sinh non tr, vi hng lot s kin nh :
Khm ph ra hng lot Cht khng sinh, th d nh Griseofulvin (1939), gramicidin S
(1942) , Streptomycin (1943), bacitracin (1945), cloramphenicol v polymicin (1947),
clotetracyclin v Cephalosporin (1948), neomycin (1949), oxytetracyclin v nystatin
(1950), erythromycin (1952), cycloserin (1954), amphotericin B v Vancomycin (1956),
metronidazol, kanamycin v rifamycin (1957)...
p dng phi hp cc k thut tuyn chn v to ging tin tin (c bit l cc k
thut gy t bin, k thut dung hp t bo, k thut ti t hp gen ...) to ra
nhng bin chng cng nghip c nng lc "siu tng hp" cc cht khng sinh cao
gp hng ngn vn ln cc chng ban u.
Trin khai thnh cng cng ngh ln men chm quy m sn xut cng nghip sn
xut Penicillin G (1942) v vic hon thin cng ngh ln men ny trn cc sn phm
khc.
Vic pht hin, tinh ch v s dng axit 6 - aminopenicillanic (6-APA, 1959) lm
nguyn liu sn xut cc cht khng sinh penicilin bn tng hp cho php to ra
hng lot dn xut penicilin v mt s khng sinh - lactam bn tng hp khc.
2.1. nh ngha khng sinh:
Cht khng sinh c hiu l cc cht ho hc xc nh, khng c bn cht enzym, c
ngun gc sinh hc (trong ph bin nht l t vi sinh vt), vi c tnh l ngay
nng thp (hoc rt thp) c kh nng c ch mnh m hoc tiu dit c cc
vi sinh vt gy bnh m vn m bo an ton cho ngi hay ng vt c iu tr.

-23-

2.2. C ch tc dng:
C ch tc dng ln vi sinh vt gy bnh ( hay cc i tng gy bnh khc - gi tt l
mm bnh) ca mi cht khng sinh thng mang c im ring, ty thuc vo bn
cht ca khng sinh ; trong , nhng kiu tc ng thng gp l lm ri lon cu
trc thnh t bo, ri lon chc nng iu tit qu trnh vn chuyn vt cht ca mng
t bo cht, lm ri lon hay kim to qu trnh sinh tng hp protein, ri lon qu
trnh ti bn ADN, hoc tng tc c hiu vi nhng giai on nht nh trong cc
chuyn ha trao i cht
2.3. n v khng sinh:
Nng lc tch t khng sinh ca chng hay nng cht khng sinh thng c biu
th bng mt trong cc n v l : mg/ml, g/ml, hay n v khng sinh UI/ml (hay
UI/g, International Unit .
n v ca mi khng sinh c nh ngha l lng khng sinh ti thiu pha trong
mt th tch quy c dung dch c kh nng c ch hon ton s pht trin ca chng
vi sinh vt kim nh chn, th d, vi penicillin l s miligam penicillin pha vo
trong 50 ml mi trng canh thang v s dng Staphylococcus aureus 209P lm
chng kim nh; vi Streptomicin l s miligam pha trong 1 ml mi trng canh
thang v kim nh bng vi khun Escherichia coli).
2.4. Hot tnh khng sinh c hiu:
Hot tnh khng sinh c hiu l c tnh cho thy nng lc km hm hay tiu dit mt
cch chn lc cc chng vi sinh gy bnh, trong khi khng gy ra cc hiu ng ph
qu ngng cho php trn ngi bnh c iu tr. c tnh ny c biu th qua
hai gi tr l:
Nng km hm ti thiu (Minimun Inhibitory Concentration - Vit tt l MIC) v
nng dit khun ti thiu (Minimun Bactericidal Concentration - Vit tt l
MBC), xc nh trn cc i tng vi sinh vt gy bnh kim nh la chn tng ng
cho mi cht khng sinh.
2.5. Ph khng khun ca khng sinh:
Ph khng khun ca cht khng sinh biu th s lng cc chng gy bnh b tiu
dit bi khng sinh ny. Theo , cht khng sinh c th tiu dit c nhiu loi
mm bnh khc nhau c gi l cht khng sinh ph rng, cht khng sinh ch tiu
dit c t mm bnh l cht khng sinh ph hp.
2.6. Hin tng khng thuc v bn cht khng thuc ca vi sinh vt:
Hin tng khng thuc: Hin tng mm bnh vn cn sng st sau khi iu tr
khng sinh c gi l hin tng khng thuc (trn phng din kim nghim, vi
sinh vt gy bnh c coi l khng thuc nu nng MIC ca cht khng sinh kim
nghim in vitro trn i tng ny cao hn nng iu tr ti a cho php i vi
bnh nhn. C hai dng khng thuc:
Kh nng khng sinh hc: Kh nng khng thuc ca vi sinh vt gy bnh c th
c hnh thnh ngu nhin trong qun th, ngha l kh nng ny c hnh thnh
mm bnh ngay khi chng cha tip xc vi mi trng cha cht khng sinh. Dng
khng thuc ny c gi l kh nng khng sinh hc. Nguyn nhn ca hin
tng ny c th do t bin ngu nhin trong nhim sc th lm trong qun th vi
sinh vt gy bnh xut hin cc t bo (hay thm ch ch cn mt vi t bo) c kh
-24-

nng khng thuc. Do , khi bnh nhn c iu tr khng sinh trong mt thi gian
nht nh th ch c cc t bo thng b tiu dit, cn cc t bo khng thuc ny vn
cn sng st, tip tc sinh trng pht trin dn b ep cho c s t bo b tiu
dit. Kt qu lm thay i hon ton bn cht vi sinh ca bnh v v hiu ha tc dng
iu tr ca thuc khng sinh .
Kh nng khng iu tr: Kh nng khng thuc ca vi sinh vt gy bnh thng
xut hin ph bin hn nhiu sau khi chng tip xc vi khng sinh, v vy trng
hp ny cn c gi l kh nng khng iu tr. Nguyn nhn ca hin tng ny
l do trong t bo vi sinh vt c cha cc yu t khng thuc R tim n (Resistance
Factor). Yu t khng thuc R c bn cht plasmid. Khi vi sinh vt sng trong mi
trng c khng sinh, cc plasmid khng thuc ca chng s c hot ho, t sao
chp tng hp ra v s plasmid mi. Chnh hot tnh ca cc plasmid ny s lm tng
sc khng cho t bo ch, nh vy chng vn c th tn ti v pht trin trong mi
trng c khng sinh. Do c bn cht plasmid nn cc yu t khng thuc R ny rt d
dng vn chuyn qua li gia cc loi gn gi nhau qua bin np, ti np hay tip hp.
Nguyn nhn hin tng khng thuc:
- Vic s dng cng loi khng sinh ko di hoc lm dng thuc khng sinh (tu tin
s dng thuc khng ng liu lng, khng ng ch nh v khng thi gian cn
thit) v tnh to ra u th pht trin cnh tranh cho cc chng vi sinh vt c kh
nng khng thuc, ng thi tr thnh liu php kch thch cc chng khng thuc ny
tng hp ra v s plasmid mi.
- Xu th s dng tu tin cht khng sinh trong chn nui, c bit l b sung vo khi
ch bin thc n gia sc, gia cm nui ly tht, trng, sa ... Khi , ngoi cc tc
dng c li d kin, chnh cht khng sinh b sung s to ra mi trng pht trin
chn lc cho cc chng mang yu t khng thuc R trn ng vt nui. Khi s dng
tht, trng, sa ... ca chng lm nguyn liu ch bin, cc chng khng thuc ny s
ko theo vo trong cc sn phm thc phm. Kt qu khi ngi tiu dng s dng cc
thc phm ny, mt mt h phi tip nhn phn d lng khng sinh trong sn phm;
nhng mt khc, nguy him hn l cc loi vi sinh vt khng thuc trong cc sn
phm thc phm thuc nhm ny c u th tn ti, pht trin cao hn v cc plasmid
khng thuc ca chng li ang trong trng thi hot ho.
C ch ca s khng thuc: C ch ca s khng thuc rt a dng v thng khc
nhau i vi tng chng vi sinh vt:
* Mt s loi vi sinh vt c kh nng khng thuc t nhin vi mt s khng sinh nht
nh, do thuc ny khng tc ng ln chng ( th d nh: nm, virus, nguyn sinh
ng vt, do trn thnh t bo khng c lp peptidoglucan nn khng chu tc ng
ca cc khng sinh lactam).
* Mt s chng vn nhy cm vi cht khng sinh tr nn khng thuc khi chng thu
nhn c mt trong cc c tnh mi nh:
C kh nng v hot hay ph hy cht khng sinh (bng cch tng hp ra cc enzym
ngoi bo lm ph v cu trc ca cht khng sinh hay lin kt vi cht khng sinh
to ra dng km hiu lc khng sinh hn).
C th t iu chnh kh nng hp th ca mng t bo cht lm gim hoc ngn nga
cht khng sinh xm nhp vo t bo cht.
-25-

C kh nng lm bin i cu trc phn t ca ni hoc v tr m cht khng sinh tc

dng vo
T iu chnh thay i ng hng trao i cht v hiu ha tc dng ca cht
khng sinh
Hin tng khng cho: Bn cnh hai hin tng khng thuc nu trn, trong thc
tin cn tn ti hin tng khng cho (hay khng nhm), ngha l mt chng khi
khng li cht khng sinh nht nh th chng cng c kh nng khng lun mt s
cht khng sinh khc cng nhm cu trc hay c cc c tnh tng ng vi cht
khng sinh y, th d nh mt s chng vi sinh vt gy bnh khng c penicillin
th cng c trng hp khng lun nhiu khng sinh - lactam khc.
Khc phc hin tng khng thuc ca vi sinh vt gy bnh: gii php trc quan v
n gin l s dng cc dng khng sinh mi. Tuy nhin, vic tm kim, pht hin v
sn xut mt khng sinh mi l c mt khi lng cng vic khng l, tiu tn rt
nhiu thi gian, nhn lc v tin bc
Trc ht cn trit tn trng ba nguyn tc s dng thuc khng sinh l:
Ch nh iu tr khng sinh ng (lm khng sinh chn ng khng sinh thch
hp ch nh iu tr; dng thuc ng liu, ng phc , thi gian iu tr; ch
pht hin sm du hiu khng thuc);
Khng lm dng khng sinh khi cha cn thit (khng lm dng "iu tr phng
nga" bng thuc khng sinh, nghim cm bnh nhn t ch nh iu tr thuc khng
sinh thay bc s);
Nghim cm s dng trn lan cht khng sinh trong chn nui v gim st cht ch
vic s dng khng sinh trong th y.
2.7. iu chnh sinh tng hp khng sinh:
Cng nh vi tt c qu trnh ln men khc, vic iu chnh sinh tng hp cht khng
sinh trn nguyn tc c th c thc hin qua hng lot c ch khc nhau, th d, c
ch cm ng, c ch kim to, c ch c ch ngc ...Trong thc tin cn phi phi
hp hng lot cc gii php khoa hc v cng ngh, c th c th phn chia thnh hai
nhm ln l:
Tuyn chn v to ra cc chng cng nghip siu tng hp cht khng sinh ;
Ti u ho thnh phn mi trng, thit b ln men v iu kin vn hnh qu trnh
ln men.
2.7.1. Tuyn chn v to ra cc chng cng nghip siu tng hp cht khng sinh :
y l thnh qu ca s phi hp ng b hng lot gii php k thut tuyn
chn ging v to chng tin tin nh: k thut gy t bin, k thut dung hp t
bo, k thut ti t hp v cc gii php k thut gen khc
Nhn chung, qu trnh tuyn chn to chng cng nghip siu tng hp khng
sinh cng thng tri qua su giai on c bn l:
- Phn lp t thin nhin.
- Nghin cu x l to cc bin chng " Siu tng hp" c hot lc cao.
- Tuyn chn s b.
- Tuyn chn li thu cc chng c hot tnh cao quy m phng th nghim.

-26-

- Th nghim v tuyn chn li trn quy m sn xut th nghim pilot.

- Th nghim v chn lc li cc chng ph hp vi iu kin ln men sn xut
ln cng nghip.
Trong cc giai on trn, bc tuyn chn li quy m phng th nghim l cng
on tuyn chn ton din v k lng nht;
Mc tiu ca qu trnh tuyn chn to bin cng cng nghip khng ch dng li
nng lc siu tng hp khng sinh ca chng, m cn nh hng ng thi vo cc
mc tiu khc nh: to ra cc bin chng tch t t cc sn phm khng mong mun,
cc bin chng tng hp ra cc sn phm hon ton mi (nht l cc sn phm c cu
trc v c tnh mong mun theo "thit k" ca con ngi), cc bin chng rt nhy
cm vi cht khng sinh hay cc chng c sc khng cao vi nhng cht khng
sinh no .... Vic tuyn chn v to chng cng nghip l cng vic lu di v tiu
tn rt nhiu nhn lc, i hi phi c tin hnh nghim tc, lin tc v thng
xuyn.
2.7.2. Ti u ho thnh phn mi trng, thit b ln men v iu kin vn hnh qu
trnh ln men:
- Vic ti u ha thnh phn mi trng ln men c vai tr rt quan trng,
quyt nh nng lc v hiu qu chung ca ton qu trnh: xc nh ngun nguyn liu
chnh, thnh phn mi trng ln men, nng tng ng ca tng cu t trong tng
thi im c th, u c xc nh qua con ng thc nghim, trn c s kim tra
trn hng lot c cht d kin chnh, cc tin cht, cc cht dinh dng khc, cc cht
ph gia k thut
. Ngun thc n cacbon thng c la chn l: cc loi bt v ht ng cc,
cm m, cm go, v khoai ty, r ng, cc loi ng ( glucoza, fructoza, maltoza,
lactoza ) dextrin, glycerin, axit axetic, manit, cc loi ru, dch thy phn g, nc
thi h sunfit
. Ngun thc n nit c th l: bt u tng, nc chit ng, cao nm men,
nc chit nm nem, pepton, cc mui NO3-, NH4+
Cc nguyn t khong a lng thng gp nh: photpho, lu hunh, ma nh,
st, canxi, kali, natri; cc nguyn t vi lng nh: ng, km, coban, molipden v
cc cht sinh trng..
.Vic thay i thnh phn mi trng, nng cc cu t v s bin thin
nng ca chng trong sut qu trnh c quan h cht ch vi hot ng trao i
cht ca vi sinh vt, v vy quan h cht ch n cc sn phm to thnh ca qu trnh.
- Ngoi ra, trong qu trnh ln men, ngi ta cn khai thc hiu qu tc ng
ca cc yu t khc trong mi trng nh: nhit ln men ti u, pH, nng oxy,
th oxy ha kh, cng sc kh, cng khuy trn dch ln men ..
Nh vy hiu qu sinh tng hp sn phm thu c bao gi cng l kt qu ca
s phi hp tc dng ca tt c cc yu t, cc iu kin trang thit b cng ngh cu
thnh nn cng ngh ln men cc sn phm .
2.8. Phn nhm khng sinh: C nhiu cch phn nhm khng sinh, l phn loi
trn c s phng php iu ch v trn c s tnh cht hoc nhng c trng ca
chng.
2.8.1. Phn loi theo phng php iu ch gm c cc nhm
-27-

- Cc khng sinh t nhin c iu ch ra bng con ng sinh tng hp.

- Cc khng sinh bn tng hp bng cch ci bin cc khng sinh nhn c t con
ng sinh tng hp (Cc khng sinh t nhin d b phn hy, d hng, tc dng
yu...)
- Cc khng sinh c iu ch ra bng con ng tng hp ha hc.
2.8.2. Phn loi theo tnh cht hoc c trng ca chng
- Phn loi theo tc dng hoc s dng ca chng (Khng sinh tc dng dit khun,
khng nm, chng ung th hoc chng virut, ph tc dng rng hoc hp, hoc khng
sinh c s dng lm thuc cho ngi, s dng trong nng nghip hoc s dng vo
cc lnh vc khc).
- Phn loi theo c ch tc dng ca chng (Cht c tc dng trn mng, tc dng
ngn cn sinh tng hp protit hoc axit nuclic hay cht ngn cn tng hp thnh t
bo).
- Phn loi theo ngun gc (Khng sinh c sn xut ra t nm mc chiu x, t vi
khun, t vi nm t to, t thc vt hoc t ng vt).
- Phn loi theo tnh cht vt l hay ha hc ca chng (Cc cht c tnh axit, tnh
bazo, lng tnh, c th ha tan trong nc hoc trong cht bo).
- Phn loi theo con ng sinh tng hp ca chng (Sinh tng hp peptit, nucleotit,
con ng axetat-propionat, axit cikciminic).
- Phn loi theo cu trc ha hc ca chng (Phn theo cc b khung c bn)
+ Cc khng sinh nhm -lactam (Cc penicillin v cepharosporin).
+ Cc khng sinh chloramphenicol.
+ Cc tetracyline (oxytetracyline, chlortetracyline).
+ Cc aminoglycozit (steptomycine, neomicine, gentamicine).
+ Cc macrolid (erythoomycine, oleandomycine).
+ Cc polien (polien-macrolit, nystatine, amphotericine B).
+ Cc anzamycin (rifamicine, rifampicine).
+ Cc lincosamydin (lincomycine).
+ Cc khng sinh peptid (gramicidin, polimycin, viomycine).
+ Cc khng sinh nucleosid (puromycine).
+ Cc polieste (monensin, nigericin, lasalocide).
+ Cc khng sinh khc (axit fusidic, fosfomycin).
2.9. ngha kinh t ca khng sinh: Khng sinh l loi thuc v cng qu gi ca loi
ngi, gip con ngi thot khi cc bnh nhim khun.
- ngha cha bnh cho ngi: Cc dch bnh nhim khun gim i tng i nhiu.
- ngha cha bnh cho th y: Thuc cha bnh cho gia sc, th y.
- ngha s dng trong nng nghip: Cc bnh v nm.
2.10. Cc thuc khng sinh nhm -lactam: L nhm khng sinh ln nht k c tc
dng tr bnh ln tn lng sn xut v doanh s.
i nt v lch s v cc s kin v nhm
a. V khng sinh nhm penicillin
- Nm 1928 Fleming pht hin thy t cu vng b nhim nm mc Penicillin notatum
=> Penicillin.
- Nm 1938-1940 nhm cc nh bc hc Oxford khi ng li vn nghin cu
Penicillin.

-28-

- Trong chin tranh th gii th 2 nhm nghin cu M-Anh thnh lp, nm 1943 bt
u sn xut Penicillin, pht hin ra chng mi Penicillin Chrysogenum c nng sut
cao; xc nh cu trc ca Penicillin.
- Nm 1945 nhm nghin cu Anh-M c gii thng Noben.
- Sheehan v Henery-Logan (1957-1959) tng hp ton phn Penicillin.
- Bachelor (1959) phn lp c 6-APA.
H

H
S

ROCHN

CH3

H2N

CH3
N

H
CH3
CH3
N

COOH

20-1
(R = CH3CH2CH=CHCH2, CH3(CH2)6,
C6H5CH2, p-OH-C6H4-CH2)

COOH

20-2
(6-APA)

- C s cng ngh sinh tng hp penicillin nh nm mc:

+ Lch s tuyn chn chng cng nghip P. chrysogenum :
Vo nhng nm u, vic nghin cu sn xut penicillin thng s dng cc chng c
hot lc cao thuc loi P. notatum v P. baculatum. Nhng t khi trng i hc
Wisconsin (M) phn lp c chng P.chrysogenum c hot tnh cao hn th chng
ny dn dn thay th v t khong sau nhng nm 50 ca th k XX n nay tt c
cc cng ty sn xut penicillin trn th gii u s dng cc bin chng
P.chrysogenum cng nghip.
- Vic tuyn chn chng cng nghip ln men sn xut penicillin trn nguyn tc
cng tri qua su giai on c bn m t trong mc 1.3.1, trong gii php k
thut c p dng hiu qu thu nhn bin chng "siu tng hp" penicillin li
chnh l cc k thut gy t bin thng nh: x l tia Rn - ghen, x l tia cc tm
v to t bin bng ho cht, th d nh Metylbis - amin (metyl -2--clo- etylamin),
N-mustar (tris - -clo- etylamin), Sarcrolyzin, HNO2, Dimetylsulfat, 1,2,3,4 diepoxybutan.
+ C ch sinh tng hp penicillin nm mc P. chrysogenum :
Theo quan im ph bin hin nay, qu trnh sinh tng hp penicillin nm mc P.
chrysogenum c th tm tt nh sau: t ba tin cht ban u l -aminoadipic, cystein
v valin s ngng t li thnh tripeptit -(- aminoadipyl) - cysteinyl - valin ; tip
theo l qu trnh khp mch to vng -lactam v vng thiazolidin to thnh
izopenicillin-N; ri trao i nhm -aminoadipyl vi phenylacetic (hay
phenooxyacetic) to thnh sn phm penicillin G (hay penicillin V, xem s tng
hp penicillin G trong hnh 1.

-29-

Hnh 1. S c ch sinh tng hp penicillin t axit L-- aminoadipic, Lcystein v L-valin

Trong 3 axit amin tin cht trn th cystein c th c tng hp bng mt trong
ba con ng l c tng hp t xerin (hnh 2), t homoxerin vi vic tun hon
chuyn ha -cetobutyrat qua oxaloacetat (hnh 3), hay t homoxerin vi s chuyn
ha - cetobutyrat qua izolecin. ng thi - aminoadipic c gii phng ra trong
s hnh 4 c th c tun hon tham gia qu trnh ngng t ban u. .

-30-

Hnh 2. S c ch sinh tng hp cystein t xerin

Hnh 3. S c ch sinh tng hp cistein t homoxerin vi s bin i cetobutyrat thnh oxaloacetat

Tuy nhin, cng c th n c gii phng ra v tch t trong mi trng (v trong qu
trnh ln men sn xut penicillin V bao gi cng pht hin thy trong dch ln men
lng ln - aminoadipic dng vng). Nh vy, qu trnh sinh tng hp penicillin,
ph thuc vo iu kin ln men c th nht nh, c th xy ra theo su ng hng
-31-

khc nhau. Do , hiu sut chuyn ho c cht - sn phm cng bin i v ph

thuc vo ng hng sinh tng hp tng ng. Theo l thuyt th hiu sut ln men
s trong khong 683 - 1544 UI penicillin/g glucoza; song, trong thc t, vi nhng
chng c hot tnh sinh tng hp cao nht cng mi ch t khong 200 UI/g glucoza.

Hnh 4. S c ch sinh tng hp - aminoadipic

Hnh 5. S c ch sinh tng hp valin

+ Tc ng ca cc thng s cng ngh n qu trnh sinh tng hp penicillin.
. S pht trin h si v c im hnh thi h si nm:

-32-

S pht trin h si nm trong qu trnh ln men bao gm:

- S tng trng v kch thc h si (tng di si, s ln ln v kch thc, mc
phn nhnh ca h si ... )
- S bin thin v s lng khm si nm trong mi trng: Thng thng, s pht
trin ny c nh gi qua hai ch tiu l: hm lng sinh khi v tc bin thin
hm lng sinh khi trong mi trng. Hai ch tiu ny c th xc nh bng nhiu
phng php khc nhau nh: hm lng sinh khi (Sinh khi ti hoc sinh khi
kh), mt quang dch ln men, tr lc lc ca dch ln men, hm lng nit, hm
lng hydratcacbon, hm lng axit nucleic ... Trong cc phng php trn, c p
dng ph bin hn c trong sn xut cng nghip l phng php xc nh qua hm
lng sinh khi.
Tc pht trin h si nm ph thuc hng lot cc yu t khc nhau trong qu
trnh ln men v s tch t penicillin thng xy ra mnh m khi h si pht trin t
trng thi cn bng. Trng thi ny c th xc lp c khi ch cung cp va v
lin tc lng thc n ti thiu cho nm mc. Thiu thc n, h si nm s t phn,
cn nu cung cp qu nhu cu trn, h si s pht trin, nhng khng tch t mnh
penicillin m tch t nhiu axit gluconic v axit malic.
c im hnh thi v cu trc h si nm: Trong qu trnh ln men, do nhiu
nguyn nhn khc nhau, s lng khm si nm bao gi cng c xu hng tng ln,
ngay c trong qu trnh ln men tnh. Trong iu kin ln men c sc kh v khuy
trn, do tc dng va p c hc vi cnh khuy v cc chuyn ng dng xoy trong
mi trng, mt mt s t gy h si nm xy ra nhiu hn v h si nm bao gi
cng c xu hng vn cun li thnh cu trc bi si cun xon, c gi l pellet.
Pellet xp (fluffy loose pellets) l dng pellet c phn bn trong h si cun thnh
khi chc v mn, lp si pha bn ngoi cun lng lo to thnh cu trc xp hn.
Pellet chc v mn (compact smooth pellets) c c im l phn si pha bn trong
pellet cun tng i cht ch ra n gn st lp si pha ngoi, lp si pha ngoi
cng cng cun chc thnh lp si mn.
Pellet rng (hollow pellets) l dng pellet c phn si bn trong b t phn to thnh
khong rng, h si pha bn ngoi cun rt cht thnh lp si mn v chc chn.
- Hiu qu chung ca qu trnh ln men c quan h hu c vi s lng, kch thc v
cu trc pellet nm. Trong thc tin sn xut cng nghip, ngi ta thng iu chnh
cc thng s cng ngh theo hng u tin to ra dng pellet nh v mn, hn ch
to pellet xp v ngn nga hnh thnh cc pellet rng. iu kin cng ngh tng
ng vi mc tiu trn thng p dng l : t l cy ging 10%, vi mt dch ging
(2-10).1011 bo t /m3; phi hp iu chnh gia sc kh v khuy trn m bo
cung cp oxy ha tan d so vi nhu cu tng ng vi thi im ln men, v to ra
pellet mn v nh (kch thc pellet thch hp nht khong 0,2 - 0,5mm), trong iu
kin cn i vi nhu cu tit kim mc tiu tn nng lng do khuy trn.
. c tnh nhit ng ca dch ln men:
Trong cc thit b ln men dung tch ln c sc kh v khut trn, thc t khng th
xc lp c s ng u ti khp cc vng th tch lm vic ca thit b. Ti cc
vng chy ri (vng gn cnh khuy), tc trao i nhit, tc chuyn khi xy ra
mnh m hn. Cn ti cc vng chy mng (vng st thnh thit b, vng gn cc ng
-33-

xon trao i nhit, vng km hiu qu hay vng cht ca thit b) tc chuyn
khi hay tc truyn nhit cng gim i. Ngoi ra, ti nhng khu vc nht nh ca
thit b c th xut hin vng xoy cc b hay cc dng chy th cp lm thiu ht v
hm lng oxy ha tan.
Cc yu t nu trn y s tc ng trc tip n nng lc sinh tng hp ca chng,
hiu qu chuyn ha to sn phm v hiu qu kinh t chung ca ton qu trnh ln
men. Thc t thng chn ch khuy trn d trn mc yu cu.
. Thnh phn mi trng ln men:
Mi trng c s ln men penicillin, vo thi k u trong nhng nm 40 - 50, l
mi trng lactoza - nc chit ng, vi thnh phn chnh nu trong bng 2.1.
Ngun c cht chnh: l lactoza c th c thay th tng phn hoc ton b bng cc
c cht khc nh: cc loi ng hexoza, ng pentoza, disaccarit, dextrin hay thay
th bng du thc vt. Trong cc c cht nu trn, hiu qu cao hn c vn l glucoza.
Ngoi ra, khi s dng du thc vt lm cht ph bt phi xt n hiu ng nm
mc s dng mt phn du thc vt lm ngun cung cp thc n cacbon, tnh ton
iu chnh nng glucoza trong mi trng ln men (v c s cn tr qu trnh
chuyn khi do nh hng ca du ph bt).
Ngun cung cp thc n nit: c th s dng l bt u tng, bt ht bng,
cc loi du cm. Nhu cu v thc n nit cng c th c p ng bng cch cung
cp lin tc (NH4)2SO4, nhng duy tr nng thp, khong 250 - 340g/l (nu d
tha hiu qu sinh tng hp penicillin s gim, nu thiu s xy ra hin tng t phn
h si) .
Hm lng cc cht khong b sung: c tnh ton, ph thuc vo lng dch
chit ng s dng;
pH mi trng c iu chnh trc khi thanh trng, sau trong sut qu
trnh ln men c gim st cht ch v iu chnh theo yu cu cng ngh.
Nng tin cht to nhnh:Trong qu trnh sinh tng hp penicillin, vic kt
gn mch nhnh ca phn t penicillin khng mang tnh c hiu cht ch. Nh vy,
nu duy tr nng tin cht to nhnh cn thit phenylacetat (hoc phenooxyacetat)
s cho php thu nhn ch yu mt loi penicillin G trong dch ln men (hoc penicillin
V). Theo l thuyt, nhu cu v phenylaceta l 0,47g/gam penicillin G (hoc
phenooxyacetat l 0,50g/gam penicillin V ). Cn ch c hai cu t trn thc cht u
gy c cho nm nn ngi ta thng la chn gii php b sung lin tc cu t ny
v khng ch cht ch nng theo yu cu, khng lm suy gim nng lc ln men
ca chng sn xut.
. iu kin tin hnh ln men:
Nhit l thng s c nh hng ln n s pht trin ca nm mc, kh nng sinh
tng hp v nng lc tch t penicillin ca chng. Nhn chung nm mc pht trin
thun li hn di nhit khong 300C. Tuy nhin, di nhit ny tc phn
hu penicillin cng xy ra mnh m. Trong thc t, giai on nhn ging sn xut
ngi ta thng nhn di nhit 300C; sang giai on ln men thng p dng mt
trong hai ch nhit l :
Ln men mt di nhit : Thng duy tr nhit trong sut qu trnh ln men
di nhit 25 - 270C.
-34-

 Ln men hai ch nhit : Giai on ln men bt u tin hnh 300C cho n

khi h si pht trin t yu cu v hm lng sinh khi th iu chnh nhit sang
ch ln men penicillin di nhit 22 - 250C (c cng ngh iu chnh xung 22
- 230C, gi nhit ny tip hai ngy ri chuyn sang ln men tip 250C cho n
khi kt thc qu trnh ln men).
pH mi trng thun li cho s pht trin h si v cho qu trnh sinh tng hp
penicillin thng dao ng trong khong pH = 6,8 - 7,4. Tuy nhin iu kin pH cao
xu hng phn hu penicillin cng tng ln. V vy, trong sn xut pH mi trng
thng c khng ch cht ch gi tr la chn trong khong pH = 6,2 - 6,8.
Nng oxy ho tan v cng khuy trn dch ln men: Vi nhiu chng nm
mc, nng oxy ha tan thun li cho qu trnh sinh tng hp penicillin dao ng
quanh mc 30% nng oxy bo ha.
Nng CO2 trong dch ln men mc nht nh cng cn thit cho qu trnh ny
mm ca bo t nm mc; tuy nhin nu nng CO2 qu cao s lm cn tr qu
trnh hp thu v chuyn ho c cht ca chng, ngha lm lm cn tr qu trnh sinh
tng hp penicillin.
. S tch t v phn hu penicillin:
Trong qu trnh ln men, do nhiu nguyn nhn khc nhau, trong c nh hng ca
nng penicillin tch t trong mi trng ngy cng tng, lm cho nng lc sinh
tng hp penicillin ca chng c xu hng gim dn theo thi gian ln men. ng
thi, ph thuc vo nhit v pH mi trng, mt phn lng penicillin tch t cng
b phn hu theo thi gian.
Nhm gim tn tht trn, ngay sau khi kt thc qu trnh ln men cn x l thu sn
phm sm hoc c gii php h thp nhanh nhit dch ln men.
+ Quy trnh ln men trong cng nghip:
. c im chung:
Cng ngh ln men sn xut penicillin mang nt c th ring ca tng c s sn xut
v cc thng tin ny rt hn ch cung cp cng khai, ngay mi bng sng ch thng
cng ch gii hn nhng cng on nht nh; v vy rt kh a ra c cng ngh
tng qut chung. Theo cng ngh ln men ca hng Gist-Brocades (H Lan), ton b
dy chuyn sn xut thuc khng sinh penicillin c th phn chia lm bn cng on
chnh nh sau (xem s hnh 6)
Ln men sn xut penicillin t nhin (thng thu penicillin V hoc penicillin G) .
X l dch ln men tinh ch thu bn thnh phm penicillin t nhin.
Sn xut cc penicillin bn tng hp (t nguyn liu penicillin t nhin)
Pha ch cc loi thuc khng sinh penicillin thng mi.

-35-

Hnh 6. S dy chuyn sn xut penicillin

(theo Gist-Brocades Copr. (H Lan))
. Chun b ln men :
Ging, bo qun v nhn ging cho sn xut: Ging cng nghip P.chrysogenum c
bo qun lu di dng ng kh, bo qun siu lnh 700C hoc bo qun trong
nit lng. Ging t mi trng bo qun c cy chuyn ra trn mi trng thch
hp hot ho v nui thu bo t. Dch huyn ph bo t thu t hp petri c cy
chuyn tip sang mi trng bnh tam gic, ri sang thit b phn ging nh, qua thit
b nhn ging trung gian ... v cui cng l trn thit b nhn ging sn xut. Yu cu
quan trng ca ca cng on nhn ging l phi m bo cung cp lng ging
cn thit, vi hot lc cao, cht lng m bo ng thi im hco cc cng on
nhn ging k tip v cui cng l cung cp lng ging t cc yu cu k thut
cho ln men sn xut. Trong thc tin, m bo cho qu trnh ln men thun li
ngi ta thng tnh ton lng ging cp sao cho mt ging trong dch ln men
ban u khong 1 - 5.109 bo t / m3.
Thnh phn mi trng nhn ging cn c tnh ton m bo cung cp ngun
thc n C, N, cc cht khong v cc thnh phn khc, m bo cho s hnh thnh v
pht trin thun li ca pellet.
Chun b mi trng ln men v thit b:
- Chun b mi trng ln men:
. Cn ong, pha ch ring r cc thnh phn mi trng ln men trong cc thng
cha ph hp
. Thanh trng gin on 1210C ( hay thanh trng lin tc khong 140-1460C)
hoc lc qua cc vt liu siu lc ri mi bm vo thng ln men.
Nu c tnh cng ngh ca thit b ln men cho php, c th pha ch ri thanh
trng ng thi dch ln men trong cng mt thit b. Tt c cc cu t b sung vo
mi trng ln men u phi c x l kh khun trc v sau b sung theo ch
vn hnh v khun.

-36-

- Thit b ln men: Phi c v khun trc khi a vo s dng. Thng

thanh trng bng hi qu nhit 2,5 3,0 at trong thi gian 3 gi. ng thi kh khun
nghim ngt tt c cc h thng ng dn, khp ni, van, phin lc v tt c cc thit b
ph tr khc.Trong qu trnh ln men luun c gng duy tr p sut d trong thit b
nhm hn ch ri ro do nhim tp.
- Khng kh thng c kh khun s b bng nn on nhit, sau qua
mng lc v khun hay mng siu lc .
+ K thut ln men:
. K thut ln men b mt:
p dng t lu, hin nay hu nh khng cn c trin khai trong sn xut
ln na. Gm 2 phng php:
* Ln men trn nguyn liu rn (cm m, cm ng c b sung ng lactoza)
* Ln men trn b mt mi trng lng tnh (ph bin s dng mi trng
c bn lactoza- nc chit ng)..
Do ng lactoza c nm mc ng ha chm nn khng xy ra hin tng d
tha ng trong t bo. Cn dch nc chit ng cung cp cho nm mc ngun thc
n nit, cc cht khong v cc cht sinh trng, trong phenylalanin khi b thy
phn s to thnh phenylacetic cung cp tin cht to mch nhnh cho phn t
penicillin.
Khi ln men trong mi trng lng, p dng cng ngh b sung lin tc
phenylacetic vo mi trng ln men, hm lng b sung ph thuc pH mi trng
thng l 0,2-0,8 kg phenylacetic/m3 dch ln men.Trong iu kin , lng
penicillin G c tng hp tng r rt cn hm lng cc penicillin khc cng gim
i. hn ch qu trnh oxy ha tin cht, thng phi b sung vo mi trng mt
lng nh axit axetic. Trong k thut ln men lng gin on khng iu chnh pH
mi trng thng tng nh, sau tng i n nh v vo cui qu trnh ln men
thng trong khong pH = 6,8-7,4. Khi s dng c cht chnh l lactoza, ngi ta
xc nh c penicillin chie c tng hp v tch t mnh m trong mi trng khi
nm mc s dng ng ny v khi lactoza c du hiu cn kit th si nm cng
bt u t phn. V vy ngi ta thng kt thc qu trnh ln men vo thi im sp
ht ng lactoza.
. K thut ln men chm:

-37-

-38-

-39-

+ Hiu qu kinh t chung ca qu trnh ln men :

Nng lc sinh tng hp v tch t penicillin trong dch ln men l kt qu ca mi
tng tc ng thi ca hng lot yu t cng ngh nh: hot tnh sinh tng hp ca
chng, cng ngh ln men p dng, cht lng nguyn liu, c tnh thit b v nng
lc p ng cc yu cu cng ngh ca thit b, ch gim st v iu chnh cc
thng s cng ngh, nng lc v k nng vn hnh ca cng nhn.... Vi ngun c
cht chnh l glucoza v ln men theo phng php chm, h s phn b nguyn liu
d tnh khong 25% glucoza c nm mc s dng tng hp h si, 65% ng
c s dng duy tr s sng st ca h si, cn li ch khong 10% c nm mc
s dng tng hp penicillin. H s s dng thc n nit v lu hunh tng hp
penicillin tng ng l 20% v 80%. Nng penicillin G trong dch ln men nhng
nm 80 - 90 ca th k XX t khong 80.000 UI/ml (tng ng nng sut khong 40
- 50 kg penicillin G/ m3 dch ln men )
- X L DCH LN MEN V TINH CH THU PENICILLIN T NHIN:
Cng on x l dch ln men v tinh ch thu penicillin t nhin c tm tt trong s
hnh 2.9 , bao gm cc cng on chnh sau y:

Hnh 6. S tm tt cng on x l dch ln men thu penicillin t nhin

-40-

+ Lc dch ln men :
Mc ch: Penicillin l sn phm ln men ngoi bo. V vy, ngay sau khi kt thc qu
trnh ln men ngi ta thng tin hnh lc ngay gim tn hao do phn hu
penicillin v gim bt kh khn khi tinh ch, do cc tp cht to ra khi h si nm t
phn.
Thit b lc: ph bin l thit b lc ht kiu bng ti hoc kiu thng quay. Thng
thng, ngi ta ch cn lc mt ln ri lm lnh dch ngay chuyn sang cng on
tip theo. Ch trong nhng trng hp rt c bit mi cn phi x l kt ta mt phn
protein v lc li dch ln th hai. Hin tng t phn h si nm thng ko theo hu
qu lm cho dch kh lc hn.
Thu hi sinh khi nm: Phn sinh khi nm c ra sch, sy kh v s dng ch
bin thc n gia sc.
+ Trch ly :
Penicillin thng c trch ly dng axt ra khi dch lc bng dung mi amylacetat
hoc butylacetat pH = 2,0 - 2,5, nhit 0 - 30C. Nhm hn ch lng penicillin b
phn hu, qu trnh trch ly c thc hin trong thi gian rt ngn trong thit b trch
ly ngc dng lin tc kiu ly tm nhiu tng cnh. ng thi, trong thi gian trch ly
cn gim st cht ch cc thng s cng ngh nh: nhit pH, v khun.... hn
ch tn tht do phn hu penicillin. Dch ln men sau khi lc c bm trn ng thi
vi dung dch H2SO4 hoc H3PO4 long c b sung thm cht chng to nh v bm
song song cng vi dung mi trch ly vo trong thit b. T l dch lc: dung mi
thng chn trong khong 4 - 10V dch lc /1V dung mi. Trong mt s cng ngh,
nhm ci thin cht lng sn phm, ngi ta c th p dng phng php trch ly hai
ln dung mi, vi ln u trch ly penicillin bng amylacetat hoc butylacetat; tip
theo penicillin li c trch ly ngc sang dung dch m
pH = 7,2 - 7,5,
thng l dung dch KOH long hoc dung dch NaHCO3; sau penicillin li c
trch ly sang dung mi ln th 2, vi lng dung mi t hn.
+ Ty mu :
ty mu v loi b mt s tp cht khc, ngi ta thng b sung trc tip cht
hp ph vo dung mi cha penicillin sau trch ly, s dng ph bin nht l than hot
tnh. Sau than hot tnh c tch v ra li bng s dng thit b lc ht bng ti
hoc thit b lc ht kiu thng quay. Phn than sau lc c a i chng thu hi
dung mi v x l hon nguyn, phc v cho cc m sau.
+ Kt tinh, lc, ra v sy thu penicillin t nhin:
Vic kt tinh penicillin V hay penicillin G di dng mui c th c thc
hin rt n gin, bng cch b sung trc tip vo dung mi sau khi ty mu mt
lng nh kali acetat (hay natri acetat) hoc ngi ta trch ly li sang dung dch KOH
long (hay NaOH long), tin hnh c chn khng nhit thp, sau b sung
BuOH penicillin t kt tinh. Cc thng s cng ngh c nh hng ln n hiu
qa kt tinh l : nng penicillin, nng mui acetat, pH dung mi hay pH dung
dch c c, nhit kt tinh ... Sau khi kt tinh, tinh th penicillin c lc tch bng
my lc ht thng quay. m bo tinh khit cao hn, c th tin hnh ha tan v
kt tinh li penicillin. Khi sn phm t tinh sch theo yu cu, thng tinh
khit khng di 99,5%, chng c lc tnh tinh th; tip theo ra v lm kh s b

-41-

bng dung mi k nc nh izopropanol hay butylalcohl; ht chn khng tch dung

mi trn my lc bng ti ri sy bng khng kh nng n dng sn phm bt mui
penicillin. Sn phm ny, mt phn c s dng trc tip pha ch thuc khng
sinh penicillin; cn li, phn ln c s dng lm nguyn liu phc v cho vic sn
xut cc sn phm penicillin v cephalosporin bn tng hp khc. Ngoi ra, sn
xut ra cc sn phm penicillin c tinh khit rt cao, ngi ta cn phi s dng
phi hp thm mt s gii php cng ngh khc.
b. V khng sinh Cephalosporin
- Nm 1948 Brotus phn lp c chng t Cephalosporium acremonium-chng sinh
ra khng sinh Cephalosporin.
- Nm 1955 Abraham v cng s phn lp c cc cht c tc dng khng sinh t
dch nui cy ca Cephalosporium acremonium.
H
N

HOOC

HH
S

NH2

CH3

O
COOH

HOOC

CH3

H
OCH3
CH3

CH3

CH3

CH3

H
HO

OH
H
CH3

OCH3

H
N

HOOC

CH3

NH2

CH3

N
O

COOH

- Nm 1961-1962 Loder v Morin iu ch ra 7-ACA t cephalosporine v 7-ADCA

t penicillin
- Nm 1966 R.B.Wordward tng hp ton phn cephalosporin C.
- Nm 1983 tm ra cc hot cht ngn cn enzim -lactamase
H

OH
O

N
O

COOH

20-7
clavulanic acid

Tc dng khng sinh khng mnh, nhng vi liu nh c ch c -lactamase

-42-

OH H

CH3 H

(+)

NH3
H3 C

NaO3SO

(-)

COO

COONa

20-8
thienamycin

20-9
olivalic acid
O

NH2

OCH3

H
N
N
H

HOOC
O

CH3

N
O

20-10
sulfazecin

c. Danh php cc khng sinh -LACTAM

- Danh php v cc b khung c bn

-43-

SO3H

NH

NH

khung penam
(1-tia-heptam)

azetidin-2-on
-lactam

azetidan

N
O

khung clavam
(1-oxa-heptam)

khung cacbapenam
S

N
O

khung cepham
(1-tia-octam)

khung 2-cephem
(1-tia-oct-2-em)

S
S
N

N
O

khung 3-cephem
(1-tia-oct-3-em)

O khung isocepham

(2-tia-octam)

N
O

khung cacbacepham
(khung cotam)

khung oxa-cepham

Hnh 20-3: Cc khung c bn ca cc khng sinh -lactam.

- Cu trc khng gian ca khung penicillin v khung cephalosporin: 2 b khung ny
kh ging nhau k c dng trong mt phng ln trong khng gian.
H

H
H

H
S

CH3

H
O

ROCHN

CH3

N
O

H O

H
N

COOH

C
H
O

-44-

OH

H
R2
C

O
C

R1OCHN

C H

CH2R2

OH

H
N

R
C

COOH

H
H

phng
(planris)

thp
(piramidlis)

Hnh 20.4. S so snh cu trc khng gian 3 chiu ca khung penicillin (A)
v 3-cephalosporine.
* Cc Penicillin t nhin
- Khi nim v Penicillin t nhin: L sn phm ln men nui cy chng Penicilium
notatum v Penicilium chrysogenum , sinh ra mt lot khng sinh t nhin ch khc
nhau nhm th R
Bng 20.3. Cc Penicillin t nhin
H

H
S

CO

N
H

CH3
CH3

N
O

COOH

20-1

Ch k
hiu
F
G
X
K
O
V
N

Tn

Mch nhnh (R)

2-pentenyl-penicilline (20-1a)
CH3CH2CH=CH-CH2
Benzyl-penicilline (20-1b)
C6H5-CH2
p-hidroxi-benzyl-penicilline (20-1c)
p-HO-C6H4-CH2
n-heptyl-penicilline (20-1d)
CH3CH2CH2CH2CH2CH2CH2
almecillin (20-1e)
CH2=CH-CH2-S-CH2
pheoxi-metyl-penicilline (20-1f)
C6H5-O-CH2
4-amino-4-carboxybutyl-penicillin
H2S-CH(COOH)-(CH2)2-CH2
(20-1h)
- Sinh tng hp cc penicillin t nhin: nui cy chng ln men ly khng sinh.

-45-

- Khi nim v hiu lc khng sinh: c o bng n v UI: lng khng sinh tnh
bng mg c ch 1 mu khun gy bnh.
- Ph khng khun ca penicillin G
Bng 20-4. Ph khng khun ca penicillin G
Loi
Vi sinh vt
Nng c ch
ti thiu (g/ml).
Tn
Cu khun
Streptococcus pyogenes (A)
0,006
Streptococcus pneumoniae
0,006
Streptococcus viridans*
0,012
G
Streptococcus faecalis
2
R
Staphylococcus aureus*
0,012
A
Staphylococcus albus*
0,012
M
Starcina lutea
0,0015
Trc khun
Bacillus anthacis
0,01-0,04
Clostridium tetani
0,007-0,3
D
Clostridium welchii
0,06-0,25

Clostridium oedamatiens
0,007-0,015

Clostridium septicum
0,03
N
Clostridium histolyticum
0,03
G
Corynebaterium diphtheriae
0,02-0,6
Actinobacillus muris
0,06
Erysipelothris rhusiopathiae
0,04-0,08
Listeria monocytogens
0,2-0,6
Cu khun
Neisseria gonorrheae*
0,003
Neisseria meningitidis
0,012
G
Neisseria catarrhalis
0,012
R
Haemophilus influenzae
0,25-1
A
Trc khun
Haemophilus pertussis
0,5-2
M
Haemophilus ducreyi
0,045-0,15
Bacteroides fragilis*
16
Bacteroides melaninogenicus
0,007-0,06

Bacteroides necrophorus
0,06-0,12
M
Escherichia coli*
20
Klebsielia pneumoniae
2-100
Proteus mirabilis
8
Salmonella spp
2,5
* Sn sinh ra enzim penicillinase phn hy khng sinh.
- Cc phn ng ha hc ca Penicillin
Trong cc qu trnh kim tra cu trc ha hc ca b khung cc hp cht

-46-

CH3

H
OC

R
S

CH3

NH
CH3

ROCHN

CH

CO

N
H

CH3

HOOC

Hg2+

H2

CH3

Raney-Ni

COOCH3

HS

CH

CH

ete

HN

CH3

N-axyl-L-alanyl-D-valin

H3COOC

CH2N2

H
H

H
S

CH3

ROCHN

(OH-)

CH3

HN
COOH

COOH

CO

CH3

N
H

HOOC

CH
3

H+

CH3

CH3

pH=2

hc enzim
penicillase

COOH

COOH
R

(-CO2)

H /Hg

2+

Hg2+
(-CO2)
HS

H
S
H2 C
ROCHN

HN

HOOC

CH3

Hg2+
CH

CH3
H3C

COOH

NH2

SH
CH3

acid peniloic

D-penixillamin

+
ROCHN

H
C

CHO

COOH

(-CO2)

Acid penaldinic
ROCHN

H2
C

CHO

Andehit peniloic

Hnh 20.5: S phn hy, chuyn v ni phn t ca cc Penicilline

- Penicillamin
Tc nhn gii c kim loi nng (Pb, Cu, Hg...) v thuc cha vim khp
COOH
HC

NH2

SH

COOH
HC

M2+

H3C

CH3

NH2
M
S

CH3

20-11

phc D-penicillamin-kelat kim loai

M=Pb, Cd, Zn, Cu, Ni, Hg, Co, Au, Fe, Mn

H3C

cistein

CH3
COOH

HOOC
S

S
NH2

CH3

* CC PENICILLIN BN TNG HP
iu ch axit 6-amino-penicillin (6-APA)
-47-

CH
3

H
R

H3C

CH3

20-12

H+

COOH

- Nm 1950 Sakaguchi thng bo phn lp c enzim penicillin-acylase thy phn

c penicillin G thnh 6-APA
C6H5

H2
C

CO

H
N

CH3

H2N

CH3

Penicillin-acylase
CH3

N
O

COOH

CH3

+H2O, pH=7,5
O

C6H5CH2COOH

COOH

20-2
6-APA

20-1b
Penicillin G

- Nm 1967 thnh cng thy phn c Pencillin G thnh 6-APA

R

H2
C

CO

H
N

CH3

Cl-Si(CH3) 3/CHCl3,

200C

COOH

COOSi(CH3)3

20-16
20-11

10-13

CH3
0

PCl5/-500C

CH3

Piridin, 1/2h

CH3

CH3

H2 N

CH3OH/10-20 C

Cl

CH3

OCH3
CH3

Piridin (-HCl)
O

CH3

3h

COOSi(CH3)3

COOSi(CH3)

20-14

20-15

NH4HCO3
pH=4

H2O
H

H 2N

CH3

CH3

N
O

COOH

20-2
6-APA

Axyl ha 6-amino-penicillamic (iu ch penicillin bn tng hp)

Phng php chung:
H

H2N

R-COCl

CH3

ROCHN

CH3

-HCl

CH3

N
O

COOR

-50C

N
O

20-2
6-APA

CH3
COOR

Cc penicilin bn tng hop

R: -CH2CHCl2, -Si(CH3)3, CHPh2

-48-

O
R

6-APA

ROCHN

CH3

N
'

CH3

COOH

Bng 20-5: Cc i din quan trng nht ca penicilin bn tng hp

H

ROCHN

CH3
CH3

N
O

Stt
1

Tn
Phenethicillin (20-16)
(Broxil, Maxipen, Syncillin)

COOH

TLTK Ghi ch
[15]
1960
O CH
CH3

Propicillin (20-17)
(Baycillin, Brocillin, Ultrapen)

[16]

1961

[16]

1960

[17]

1961

[18]

1960

[19]

1961

[20]

1961

O CH
C2H5

Fenbenicillin (20-19)
(Phebenicillin, Penspek)

O CH
C6H5

Cl

Clometocillin (20-19)
(Rixapen)

H
C

Cl

OCH3

OCH3

Methicillin (20-20)
(Azapen, Belfacillin, Celbenin)

OCH3

Ancillin (20-21

C6H5

Nafcillin (20-22)
(Naftopen, Unipen, Nafeit)

OC2H5

Oxacillin (20-23)
(Micropenin, Oxabel, Stapenor)
N
O

-49-

CH3

Cloxacillin (20-24)
(Bactopen,
Methocilin)

Cl

N
Cl

Dicloxacillin (20-25)
(Brispen, Stampen, Veracillin)

11

Floxacillin (20-26)
(Culpen, Floxapen, Ladropen)

1965

[22]

1965

Ampicillin (20-27)
(Amfipen,
Amipenix,
Domicillin)
Epicillin (20-28)
(Dexacillin, Spectacillin)

[23]

1961

[24]

1969

[25]

1964

[26]

1963

[27]

1966

CH3

13

[22]

CH3

Cl
Cl

12

1961

CH3

10

[21]

Cloxapen,

H
C
H2N
H
C
H2N

14

Amoxicillin (20-29)
(Amoxilline, Amolin, Aspenil)

H
C

HO

H2 N

15

16

Azidocillin (20-30)
(Globacillin,
Longatrew,
Nalpen)

H
C
N3
Cl

Pirazocillin (20-31)

CH3
N
N
Cl

17

Betacin (20-32)

H
C
H2C

18

Metampicillin (20-33)
(Ocetina, Magnipen, Bonopen)

H
C
N

19

NH2

Suncillin (20-34)

CH2

H
C
HN

-50-

SO3H

20

Azlocillin (20-35)
(Alzin, Securopen)

H
C
HN

21

Mezlocillin (20-36)
(Baycipen, Baypen, Mezlin)

Piperacillin (20-37)
(Isipen, Pentcillin, Pipril)

C
O

HN

1974

[30]

1976

[31]

1965

[32]

1964

[33]

1970

[34]

1964

[25]

1963

C
O

[29]
SO2CH3

H
C

1971

NH

H
C
HN

22

C
O

[28]

N
C2H 5

23

24

Hetacillin (20-38)
(Uropen, Versapen, Natacillin)
HN

H3 C

CH3

Cyclocillin (20-39)
NH2

25

Carbenicillin (20-40)
(Gripenin-O, Carbapen)

CH
COOH

26

Sulbenicillin (20-41)
(Kedacillin, Sulpenlin)

CH
SO3H

27

Ticarcillin (20-42)
(Monopen, Ticar, Ticillin)

CH
S
COOH

28

Quinacillin (20-430

29

Furbenicillin (20-44)

COOH

H
C
HN

C
O

H
N C
O

- Cc kt lun rt ra lin quan n cu trc v tc dng ca cc penicillin bn tng hp

+ Mch nhnh c cha nhm NH2 => Ph khng khun m rng n gram (-).
+ Mch nhnh c ng phn D c tc dng mnh hn R.
+ Trong mch nhnh c nhn phenyl th th tc dng gim i, tr trng hp OH th
para nh amoxicillin.
- C ch tc dng ca ch phm kt hp gia khng sinh penicillin v axit clavulamic.

-51-

CH CO
NH2

H
N

CH3

axit clavulanic

CH3

N
O

enzim -lactamase

COOH

Ampicillin, R=H
Amoxillin, R=OH

O
C

CH

H
N

COOHHN

NH2

Enzim -lactamase

CH3

CH

Axit penicillic

COOH

Cc penicillin este
- Cc este tiu biu ca ca penicillin v ang s dng trong iu tr
Bng 20-6. Cc este quang trng ca penicillin t nhin v penicillin bn tng hp
H

R1OCHN

CH3
CH 3

N
O

STT
1

2
3

COOR2

Tn
R1
Penethamate (20-50)
(Alivin,
Estopen,
Neopentil)
Lactopen (20-51)

H2
C

H2
C

Penamecillin (50-52)
(Wy-20788,
Havapen,
Maripen)
Pivampicillin (20-53)
(Inacilin,
Maxifen,
Pondocillin)
Bacampicillin (50-54)
(Ambaxin,
Bacacil,
Penglobe)
Talampicillin (20-55)
(Talat,
Talpen,
Yamacillin)

H2
C

NH2

R2
-CH2CH2N(C2H5)2

TLTK
[38]

-CH2CH2N(CH3)2
-CH2OCOCH3

[39]

-CH2OCOCH(CH3)2 [40]

C
H
NH2
C
H

[41]
CH(CH3)OCOOCH3

NH2

[42]

C
H

NH2

Lenampicillin (20-56)
(Takacillin, Varacillin)

H2
C

C
H

CH3

[43]

O
O

Carindacillin (20-57)
(Carindapen, Geocillin)

-H

CH
C
O

-52-

[44]

Carfeccillin (20-58)
-H
[32]
CH
(Carbapen,
Carbecin,
C
O
Pyopen)
O
Mt s phng php chung iu ch este ca penicillin, c th quan st c
trong hnh 20-8

R1OCHN

CH3
CH3

N
O

COOY

CH3
CH3

N
O

ClCOOR2

R2N2
ete/200C

R1OCHN

CH3

N=
S

COOR2

CH3

C
2

DCD
N

R1OCHN

R2OH
CHCl3

CH 3

Cc este cua penicilin

COOCOOR

R2-OH/00C

COOH

R1OCHN

CH3

R2=C2 H5, CH3, CH2C6H5

R1=C6 H5CH2-, C6H5OCH2-

A
S

CH 3

DMF hoc xeton

R1OCHN

Y=Na, K, Et3NH(+)
R1=C6H5CH2-,C6H5OCH2R2-X (X:Cl, Br)

R1OCHN

CH3
CH3

COOY

piridin hoc Et3N

0-50C
R1OCHN
R2OH

CH3

R2OH

COOH

CH3
CH3
COO
H

Hnh 20-8: Cc kh nng tng hp este ca penicillin

Cc dn xut th v tr 6 ca penicillin
- Gii thch tnh khng -lactam ca cc hp cht cha nhm th 6
+ a nhm th vo v tr C-6 u dn n gim tc dng, tr duy nht nhm
metoxy v tr 6.
+ Nhm metoxy lm gim hot lc nhng bn vi -lactamse.
- Hai cht tiu biu:
S
O
C

OCH3H

HN
COONa

CH3
CH3

N
O

COONa

20-59
temocillin [47]
(temopen)
CHO
O
C

NH

HN
O
O

C2H5

O
N

CH 3
CH3
COOH

20-60
tomadicillin

-53-

 Axit Clavulanic
OH
H

N
O

COOH

20-7
Clavulanic acid49
(Augmentin, Ciblor, Llavocin)

- Tc dng: Khng sinh yu, nhng nng thp ngn cn c cc enzim

khng li tc dng ca penicillin v cephacillin v enzim -lactamase.
- Ch phm kt hp: Augementin.
2.11. Cc khng sinh khc
Cc khng sinh khung Carbapenem
Cc khng sinh khung carbapenem tm thy c chia thnh 2 phn nhm, da vo
s khc nhau v cu hnh khng gian ca n, hai nhm l: Cc tienamic v cc axit
olivanic.
Cc tienamicin
HO

S
NHR

H3 C

N
O

COOH

20-61, R=H tienamicine

20-62, R=CH3CO (N-acetyl-tienamicine)
20-63, R=CH2-CH=NH (N-formimido-tienamicin)

Cc axit olovanic
H3 C

O
NaO

S O
O

COO(-)Na(+)

20-64, R=-SO-CH=CH-NH-COCH3 (E) (MM4550)

20-65, R=-S-CH=CH-NH-COCH3 (E) (MM13902)
20-66, R=-S-CH2-CH2NH-COCH3 (MM17880)

Cc khng sinh nhm Cephalosporin

+ Vi nt v Cephalosporin t nhin

-54-

(-)

H
N

OOC

H 3N

(+)

O
COOH
O

pH>7.5
20-3: R=OCOCH3
20-67: R=OH
<
20-68: R=H

pH=1-2

O
O

20-69
HOOC

CH3

CH3
OCOCH3

(-)

H
N

OOC

H3N

CH3

(+)

CH3

CH 3

N
O

CH 3

CH3

20-70

COOH

20-1h

HO

OH
H
CH 3

OCOCH 3

- Qa trnh sinh tng hp penicillin v cephalosporin

HOOC

H2 N

SH

H2N

CH3

COOH
NH2

HOOC

COOH

-aminoadipic

H
N

HOOC

NH2

CH3

L-valin

L-cistein

SH

H
N

O
O

Tripeptid

H
N

HOOC

COOH

H
N

HOOC

CH3

O
H2N

OCOCH3

O
H2N

N
O

COOH

Hnh 20-9: Qa trnh sinh tng hp cephalosporin t nhin

+ Cc cephalosporin bn tng hp
Nhng nt c trng
. Cu trc ha hc ca cephalosporin
Cng thc tng qut
-55-

CH3
COO
H

R2

N
H

N
R1

20-71

COOR2

. Mt s tnh cht ha hc c trng ca cc hp cht nhm cephalosporin

Cc hp cht cha khung cephalosporin c cc c tnh sau:
- Tnh khng bn vng ca vng -lactam.
- Cc tc nhn i nhn Nu (bazo) m vng -lactam to ra cc dn xut ca
cephalosporoic khng c hot tnh khng sinh.
S
ROCHN
N
CH2R'

20-71

COOH

Cephalosporin
amidase
H2O/axylase

esterase

H2 N

ROCHN
N

N
CH2R'

CH2OH

COOH

COOH

desaxetyl cephalosporin

axit 7-aminocephalosporiamic
H+

H+

(-H2O)

(-H2O)
S

ROCHN

H2 N

N
O

lacton ca axit
desaxetyl 7-aminocephalosporamic

ROCHN

ROCHN

COOH

lacton ca axit
desaxetyl cephalosporin

--lactamase
hoc
OH-,H+

HN

COOH

CH2R'

CH 2

COOH

axit cephalosporoic

COOH

axit anhidriodesaxetyl
cephalosporoic

. S lin quan gia cu trc v tc dng;

-56-

- Tc dng khng sinh lun i km vi vng -lactam, m vng mt tc dng.

- Nhm acyl lm thay i tc dng khng khun ca phn t.
- S khng -lactamase nh vo cc nhm R v R2, trong R c NH2; SO3H lm
tng bn vi -lactamase.
- R1 lm thay i tnh cht dc ng hc ca phn t.
. Phn loi cc cephalosporin
- Phn theo cu to ha hc
- Theo c tnh tc dng theo 4 th h:
+ Th h 1: D b phn hy bi cephalosporinase; cc cht R1=CH2OCOCH3; R
l thienyl, tetrazolyl l nhng cht nhy cm, d b phn hy.
+ Th h 2: Gm cc cht khng li -lactam, cc cht trn R-CO c cha OH
(mandelic axit) -> ngn cn khng cho cc enzim n gn. Thi gian bn phn hy
75-80.
+ Th h 3: Tc dng khng -lactam mnh hn th h 2. Tc dng mnh hn
trn vi khun Gram (-). Nng MiC ti thiu thp hn. C kh nng khuch tn
tt ti nhng ni m TH1 v 2 khng n. Thi gian bn phn hy di hn.
+ Th h 4: Gioongs th h 3, nhng: Khng -lactam mch hn, tc dng trn vi
khun Gram (-) mnh hn.
iu ch cc cephalosoprin bn tng hp
Gm 2 giai on:
- iu ch ra cht trung gian 7-ACA v 7-ADCA.
- Acyl ha 7-ACA hoc 7-ADCA.
R2

H2N

R2

N
H

R
N

N
R1

R1

COOR3

COOR3

Bng 20-7. Cc cephalosporin bn tng hp quan trng

O
R

R2

N
H
N
R1

O
COOR3

Th Tn thng
h
dng

1
I

2
Cephalothin
(20-93)

R1

R R3
2

4
OCOMe

-57-

5 6
H H

C vo
c th,
NC vi
-lac..
7
Tim
nhy cm

TLT
K

8
[68]

Cephaloridin
e
(20-94)

H H

Tim
[69]
nhy cm

OCOMe

H H

Tim
[70]
nhy cm

OCOMe

H H

OCOMe

H H

Tim
[71]
nhy cm
Ung
[72]
nhy cm

+
N

I
I

Cephapirin
(20-95)
Cephacetriel
(20-96)
Cephaloglyci
n
(20-97)

Cephalexin
(20-98)

Cefadroxyl
(20-99)

Cephradie
(20-100)

Cefazolin
(20-101)

NC
NH2

NH2

NH2

-Me

H H

Ung
[73]
nhy cm

-Me

H H

Ung
[74]
nhy cm

-Me

H H

Ung
[75]
nhy cm

H H

Tim
[76]
nhy cm

H H

Ung
[77]
nhy cm

HO

NH2

N
N

N
S
S

HN

Cefaclor
(20-102)

NH2

-OCH3

-58-

Me

Cefroxadie
(20-103)

Cefatrizie
(20-104)

NH2

-OCH3

NH2

NH

H H

Ung
[78]
nhy cm

H H

Tim
[79]
nhy cm

H H

Tim
[80]
nhy cm

H H

Tim
[81]
nhy cm

H H

Tim
bn vng

[82]

H H

Tim
bn vng

[83]

H H

Tim
bn vng

[84]

H H

Tim
bn vng

[85]

S
N
HO

NH2

Cefaparole
(20-105)

N
S

Me

HO

Cefazedone
(20-106)

II

Cl

Me

N
N

OH

Cefamandol
(20-107)

Cl

N
N
Me

II

OCHO

Cefamandol
Nafete
(20-108)

N
N
Me

II

OH

Cefonicid
(20-109)

N
N
CH2SO3H

II

Cefazaflur
(20-110)

F3CS
S

N
N
Me

-59-

II

II

Ceforanide
(20-111)

Cefuroxime
(20-112)

II

Cefoxitin
(20-113)

II

Cefotetan
(20-114)

H H

Tim
bn vng

[86]

NH2

N
CH2COOH

OMe

OCONH2

H H

Tim
bn vng

[87]

OCONH2

O H
C
H

Tim
bn vng

[88]

Tim
bn vng

[89]

Tim
bn vng

[90]

H H

Tim
bn vng

[91]

H H

Tim
bn vng

[92]

H H

Tim
bn vng

[93]

H H

Tim
bn vng

[94]

NH2

N
N
Me

C C

NH2

Cefminox
(20-115)

HOOC

II

HOOC

N
N
Me

III

O H
C
H
3

SO3H

Cefsulodin
(20-116)

O H
C
H

H
S

CONH2

III

Cefotiam
(20-117)

N
N

S
N

H2N

S
CH2CH2NMe2

III

Cefotaxime
(20-118)

OMe

OMe

OCOMe

H2N

III

Cefuzonam
(20-119)

S
N
S

H2N

-60-

Me

III

NOMe

Ceftizoxim
(20-120)

H H

Tim
bn vng

[95]

H H

Tim
bn vng

[96]

H H

Tim
bn vng

[97]

H H

Tim
bn vng

[98]

O H
M
e

Tim
bn vng

[99]

O H
M
e

Tim
bn vng

[100]

H H

Tim
bn vng

[101]

H H

Tim
bn vng

[102]

N
H2 N
S

III

NOMe

Cefmenoxim
(20-121)

N
H2 N

Me

III

OH

Cefpiramide
(20-122)

N
CONH

S
N
Me

Me
OH

III

Cefoperazon
e
(20-123)

N
C2 H5

O
NH

HO

III

Cefbuperazo
ne
(20-124)

Me

CONH

N
N
Et

O HO

CH3

Me

III

Cefmetazol
(20-125)

NCH2C

S
N

S
N
Me

III

NOMe

Ceftriaxone
(20-126)

Me

OH

N
S

N
H2 N
S

III

NOMe

Ceftiofur
(20-127)

O
S C

H2 N
S

-61-

III

Me

NOMe

Cefodizime
(20-128)

H H

Tim
bn vng

[103]

H H

Tim
bn vng

[104]

H H

Tim
bn vng

[105]

H H

Ung
bn vng

[106]

NOCH2CO

H H

Ung
bn vng

[107]

NOH

H H

Ung
bn vng

[108]

H H

Tim
bn vng

[109]

H H

Tim
bn vng

[110]

H H

Ung
bn vng

[111]

N
COOH

H2 N
S

III

Me

Ceftazidime
(20-129)

COOH

N O
N

Me

H2N
S

III

Cefpimizole
(20-130)

CONH
N

COOH

N
H

III

SO3H

NOMe

Cefetamet
(20-131)

-Me

N
H2 N
S

III

Cefixime
(20-132)

N
H2N
S

III

Cefdinir
(20-133)
N
H2N
S

III

NOCH3

Cefditoren
(20-134)

N
Me

H2N
S

III

NOMe

Cefteram
(20-135)

N
N

Me

H2 N
S

III

NH2

Cefprozil
(20-136)

Me

HO

-62-

III

OCONH2

Me

Cefcapenepir
oxil
(20-137)

H A

Ung
bn vng

[112]

H H

Ung
bn vng

[113]

H B

Ung
bn vng

[114]

H H

Tim,
ung
bn vng

[115]

H H

Tim
bn vng

[116]

H H

Tim
bn vng

[117]

H H

Tim
bn vng

[118]

N
H2N
S

III

HOOC

Ceftibuten
(20-138)

N
H2N
S

III

Cefpodoxim
eProxetil
(20-139)

NOMe

OMe

N
H2 N
S

III

NOMe

Cefozopram
(20-140)

N
H2 N
S

IV

NOMe

Cefepime
(20-141)

Me

N
H2 N
S

IV

NOMe

Cefpirome
(20-142)
N
H2 N

IV

NOMe

Cefclidin
(20-143)

NH2

+N

H2 N
S

A=

B=

-63-

OCO C(Me)3

Me

O
Me
O

O
Me

iu ch mt s nguyn liu trung gian cha khung cephem: Axit 7-aminocephalosporanic (7-ACA, 20-6) v 7-amino-desaxetoxi-cepha-losporanic (7ADCA,20-72)
a. iu ch axit 7-amino-cephalosporanic (20-6,7-ACA)
* Phng php ca R.B Morin (1962) i t cephalosporin C
HOOC
H 2N

HOOC
O
H

NOCl

N
H

NH O
NO

CH2OAc

20-3

N R
H

COOH

20-73

HOOC

HOOC

+
N2

O
NR
N R

20-74

H
+

H /H2O

20-75

H2 N

R=

N
CH2OAc

20-6

COOH

CH2OAc

O
COOH

*Phng php ca B.Fechting

-64-

S
R1OCHN

(CH3)2SiCl
cephalosporin

20-76

CH2R

20-77

COOSi(CH3)3
S

POCl3

R1 C N

R2OH

Cl

piridin
CH2Cl2

R1 C N
OR2
N

N
CH2R

20-78

COOSi(CH3)3

pH=5

COOSi(CH3)3

H 2N
N

N
CH2R

CH2R

20-6
7-ACA
trong do

20-79

H2N

(ng im)

CH2R

COOH

20-80

R1= HOOC-CH(NH2)(CH2)3

COOSi(CH3)3

R=OCOCH3, R2=C2H5

* Phng php dng enzim thy phn

b. iu ch axit 7-amino-3-deaxetoxi-cephalosporin (20-72, 7-ADCA)
* Phng php ca R.B.Morin-B.G.Jackson (1962-1963)

-65-

O
CHN

CH3

O
CHN

CH3

CH3

este hoa

O
H

20-81

G-penixillin C6H5CH2

CH3

KMnO4

COOH

20-85

COOR1

CH3

CHN

V-penixillin C6H5OCH2

CH3

N
O

COOR1

20-83

oxi hoa

R1: p-NO2C6H5CH2
CCl3CH2
(Me)3Si
CH3CO2OH
CH3CN

O
R

O
CHN

CH3

Este hoa

O
CHN

OHAc

O
CHN

CH3

C
CH2

CH3
CO2 R1

20-86

O
H

20-88

NHC

OCOCH3

1.PCl5
2.ancol hoa
3.HOH
4.p-TsOH

CH3

CO 2R1

20-88

H
NHC

CO2R

O
S

Ac2O/Toluen

CH3

20-84
+

COOH

O
CHN

20-82

Marin-Jackson
CH3

CH3

S(--izome)
O

CH3

CH3

20-89

CO2 R1

loai nhom
bao ve este

.p-TsOH H2N

CO 2R1

H2N

N
N
CH3

CH3

20-89

20-89

CO 2R1

CO 2R1

Hnh 20-11. Qa trnh chuyn ha penicillin thnh 7-ACDA (20-72)

*Phng php J.J.Koning (1975)
O
RCO3H
penixillin G
(20-1b)

CH3

S
C6H5H2C

CO

CH3CN

N
H

CH3
(H 3C)3SiN

CH3

OSi(CH 3)3

piridin, HBr
80%

COOH

20-82
S

S
C6 H5 H2 C

CO

N
H

PCl5, ROH

H2 N
N

N
CH3

20-91

>90%

CH3

O
COOH

COOH

7-ADCA,20-72

Hnh 20-90. Qa trnh chuyn ha penicillin thnh 7-ACDA (20-72)

* iu ch 7-ADCA i t cephalosporin C (20-3)
-66-

. iu ch cc cephalosporin bn tng hp
- Axyl ha nhm 7-amino ca 7-ACA hoc 7-ADCA
- a cc nhm th vo C-7, C-3 hoc C-3.
a. Cc cephalosporin bn tng hp l dn xut N-axyl ha ca 7-ACA, 7-ACDA
Tin hnh trong 3 bc (este ha-axyl ha-thy phn)
S

este ha

H2 N
N

bao v nhm
cacboxylic

CH2R

O
COOH

axyl ha

H2N

COOR'

20-93

20-6, R=OCOCH3
20-72, R=H

R=OCOCH3 hoac H
R'=-CH2CCl3, -SiMe3, -CHPh2
S

S
R''

R''-COX
R''-COOCOOR'''

CH2 R

O
C

N
H

thuy phn

R''

O
C

N
CH2 R

20-94

N
H

N
CH 2R

20-94

COOR'

COOH

R=OCOCH3 hoac H
R''=l nhng nhm th khc nhau

V d v bn tng hp cephalexin (20-98) hoc cephaloglycin (20-97)

NHR
COOH

NHR

1. NEt3
2. ROCOCl

H
N

A:
3. 7-ACA (20-6)
hoac 7-ADCA (20-72)
4. H +

220-144
R=t-BuOCO

R1

R=t-BuOCO
R1=-OAc hoac H

NH 2

1. HCOOH hoac CF3COOH

2. Amberlite LA

COOH

H
N

R1

O
COOH

B:

Zn/HCOOH
NHCOOCH2 CCl3

RHN

H 2N

1. NEt3
COOH 2. ROCOCl
3. H +
20-145

Cephaloglycin, R=OAC (20-97)

Cephalexin, R1=H (20-98)
S

O
O

20-147, R=OCOCH 2CCl3

R2=-CH2CCl3

CH 3

CH3 O
COOR2

COOCH2CCl3

7.ADCA-TCE
20-146

* Mt s cephalosporin th h I s dng ng ung:

Cephaloglycin (20-97), cephalexin (20-98), cefactor (20-102) l nhng cht c mch
nhnh l nhm D--aminoaxetyl hoc l cc dn xut c s bin i trong nhn thm
(cephradin(20-100), cephadroxil (20-99), cephatrizine (20-104), cefaparole (20105)...). tng hp cc hp cht loi ny thng s dng phng php axyl ha vi
andehit hn tp (phng php A trong hnh 20-12).
* Mt s cephalosporin th h II tiu biu:
Cefamandol (20-107) v cefomicid (20-109), cefazaflur (20-110) (Bng 20-7), trong
hai hp cht sau trn mch nhnh c axit D-mandulic. Cefamandol l hp cht khng
sinh li cc enzim -lactamase, c tc dng vi i a s vi khun gram (+). Cn
trong chun vi khun gram (-) th tc dng ti E.coli, P.mirabilis, Klebsiella
pneumoniae v Haemophilus. Nhc im ca n l ch dng c ng tim v
-67-

thi gian bn phn hy ngn (74 pht). O-formyl ca cefamandol l cefamandolnafate (20-108) cng c iu ch, cht ny c tc dng ging nh cefamandol
nhng bn vng hn.
iu ch cefamandol (20-107):
N

7-ACA
20-6

H2N

N
HS

20-148

N
CH3

CH3

20-149

COOH
OR

OR
X

H
N

N
N

20-150
R=SiMe3 hoac COCH2Cl2
X=OCOtBu hoac Cl

O
CH3
COOH

20-151
R=SiMe3 hoac COCHCl2

OH
H
N

(+)

N
O

N
O

CH3

20-107
Cefamandol COOH

Trong hp cht 20-148 c iu ch i t guanidin:

H2N

NH2

H
N NH2

1. Nitro hoa
2. Khu ha
H2N

NH

1.HNO3 loang
2.NaNO2

N3

H2N
NH.HNO3

dd NaOAc
dun si

diazo ha

(+)

N
H2N

H2S

MeI

N
N

N2

N
H

NH.HNO3

HS

N
H

HS

N
H

N
CH3

20-148

* Tng hp cefonicid (20-109)

N

OH
H
N

OH
H
N

N
HS

CH3
O

20-152

20-153

N
O

OAc

* Tng hp cefazaflur (20-110)

-68-

20-109
Cefonicid

COOH

CH3
COOH

H2N

CF 3CH2COCl

N
F3C

NH

20-109
Cefonicid

CH3
COOH

20-110
Cefazaflur

CH 3
COOH

Trong hp cht 20-154 c iu ch theo dy phn ng sau:

ICH2COOH
AgF + CS2

CF3-S-Ag

PCl3
CF3-S-CH2-COOH

CF3-S-CH2-COCl
20-154

* Mt s Cephalosporin th h III tiu biu (c cha nhm amino-tiazolyl trn mch

nhnh) gm c Cefataxime (20-118).
b. Cc cephalosporin bn tng hp l nhng hp cht c s bin i trn nguyn t C3
Mt s cht i din:
- Ceftizoxime (20-120) (th h III).
- Cefactor (20-102) (th h I).
- Cefpirome (20-142) (th h IV).
c. Cc cephalosporin bn tng hp c s bin i trn nguyn t C-7.
* Cc cephamycin t nhin
HOOC

H
C
NH2

H3CO
N
H

O
COOH

Cephamycin A, R=

C
C
OCH3H

OSO3H

Cephamycin B, R=

C
C
H
OCH3

OH

(20-158)

Cephamycin C, R= NH2

* iu ch cc cht cha khung cephamycin

-69-

Cephalosporin C (20-3)
Theo pp
Glaxo

Cephamycine (20-158)

Chiet xuat
+ este ha
H

OCH3 H

CONH

1.LiOCH3
2.t-BuOCl
N

O
CO2R''

R'N

OAc

O
CO2R''

THF-CH3OH, -800C R'N

COOR''

CONH
R
COOR''

20-161
R=OCONH2 hoac OAc
R'=R''=H

20-160
R': Phtalyl hoac t-BuOCO
R'': CHPh2

deaxyl ha
CO
S

OCH3 H

OCH3 H
S

COCl

CONH

Cl3OCOCHN

O
CO2CHPh2

CF3CONHSi(CH3)3

OCONH2

AcOHZn
CF3COOH anizol

1. axyl ha
2. CF3COOH-anizol
O

O
OCH3H
O

N
H

CO2CHPh2

COOR''
20-159
R=OAc, R''=H

CO2CHPh2

20-162

H2N

OCH3H

HN
O

20-163

R
COOH

20-113
cefoxitin

HN
O

R
COOH

7-metoxi-cephalotin

Hnh 20-13. S tm tt iu ch 7-metoxi-7-ACA (20-159) v cefoxitin (20-113)

i t
. Cc 1-oxacephalosporin
- Mt s tnh cht ca oxacephalosporin: Vic thay th S bng O lm tng sc cng
ca b khung, tng c tnh thm nc ca hp cht, lm gim gn kt vi huyt
tng, tng chc thng qua thnh t bo ca cc vi khun gram (-), bn vng vi lactamase
- i din l moxalactam

-70-

OCH3H
O
CH C N
COOH H

HO

N
N

S
N
CH3

COOH

20-169
moxalactam (113)
(Festamoxin, Moxam, Shiomarin)

Tng hp moxalactam (20-169, t 6-APA)

H

N
20-2
6-APA

CH3

R' CO N
H

CH3

CH3

H 2N
O

R' CO N
H
N
Bazo
COOR2
O
20-170
O
R'=C6H5, R2CHPh2

COOH

CH3

CH3

CH3
N
20-171

R1

COOR2

R1
O
O

R1

Cl

NH

Cl

Cl2
O

NaHCO3

CH2

20-172

CH3
COOR2

Cl

20-173

CH2

COOR2

20-174

O
COOR2

R1

OH

2. Cu2O
DMSO-H2O

a. Cl2
b. piperidin

CH2

N
H

R1
N
COOR3

C
H2

COOR3

C
H2

20-178

2. axyl ha
3. deeste ha

H
HO

S
N

O
CH C N
H
COOH

N
COOH

Hnh 20-15. S tng hp moxalactam i t 6-APA

-71-

N
Me

OMe

1. deaxyl ha

Cl

CH2

20-176 COOR
2
OMe H O

N
H

20-176

N
H

BF3, Et2O R1

20-175 COOR
2
H
O

R1

1. NaI

N
N
CH3

. Cc -lactam n vng
Nhm khng nay c pht hin ra u tin vo nm 1976. Gm 2 nhm cht
- Nocardicin A(20-180)
HOOC

O
O

H
OH

NH2
N
N
OH

O
HOOC

20-180
nocardicin A

- Nhm mnbactam
NH2

OCH3

H
N
HOOC

N
H
O

20-181
Sulfazecin

CH3

NH2

SO3H

OCH3

H
N
HOOC

N
H

20-182
isosulfazecin

CH3

SO3H

- iu ch cc mnbactam
+Ln men.
+ Chuyn ha i t penicillin G hoc cephamycin
S
H2
C CO N
H

CH3
R

O
C

H
N

OCH3

CH3
N

N
COOH

R'

Penicillin G

Cephamycin

COOH

OCH3

H2N

H2N

N
O

SO3H

SO3H

20-184

20-183
3-AMA

-72-

Tng hp mt s monobactam s dng trong iu tr

+ Aztreoman (20-185): C ph khng khun hp, ch c tc dng trn Gram (-),
nhng c hiu trn E.Coli, Klebsiella, cc loi protens. Hiu lc ca n ging nhhuw
khng sinh th h III ca cephalosporin
OH

OH

H3N

OH

H3N
Me

t-Boc

H2N

MeOH
93%

NH3

Me

SOCl2
O

+5%
90%

OMe

OH

H
N

Me

Me

MsCl, piridin

t-Boc-Cl
75-85%

80-90%

NH2

OMs

H
N

t-Boc

Me

C2H4Cl2

_
O

H
N

KHCO3

Me

1. 2-picolin-SO3 90%
2. Ionpar-extraktion
M+=Bu4N+

NH2

20-189

20-188
t-Boc

OMs

H
N

t-Boc
Me

NH2

20-191

20-190

CH3
O

97%
HCOOH 70%

CH3

NH3
N
O

20-191

COOH

Me

H3N

SO3M

NHSO3M

Me

_
SO3

N
O

20-185
aztreonam

_
SO3

Hnh 20-16: Tng hp axit 3-amino-4-metyl-monobactamic

+ Carumonam (20-193)
O

COOH

N
H2N

O
O

NH2

N
O

20-193, X=SO3H
carumonam (130)
(Amasulin, Mobactam

Ngoi cc carumonam ra ngi ta cng iu ch ra nhiu dn xut khc vi nhng

nhm th X khc nhau l nhng nhm ht in t, mang in tch m, cc phn nhm
(X) bao gm:

-73-

Monophospham: X=

OH

ankyl

Monocarbam: X= -CONHSO2NH-acyl
Monosulfactam: X= -OSO3H
Oxamazin: X= -OCH2COOH

HN

N-(tetrazol-5-yl)-azetidion: X=

d. Khng sinh Chloramphenicol

-Lch s: c Bartez v Ehrlich ng thi phn lp ra t mi trng cy x khun
Venezuelea nm 1948 do loi Streptomyces Venezuela. Sau cht ny c nhiu
x khun khc sn sinh ra. Sn phm hin c trn th trng u do tng hp ha
dc.
- Hai thuc c s dng:
OH

Cl

OH

H
N

Cl
H
N

Cl

Cl

O
O2N

OH

O
H3CO2S

20-194
chloramphenicol (133)
(chloromycin, chlorocid, leucomycin)

OH

20-195
thiamphenicol(134)
(thiamcol, thionicol, thiocymetin)

Cc dn xut este ca chlorampenicol

OH
O2N

H
CH CH N C
O
H2C

CHCl2
COR

Mt s tnh cht v dc hc
- C ch tc dng: Gn c phc hi vo tiu phn 50S ca riboxom ca vi khun c
tc dng km khun v dit c mt s vi khun.
- Dc ng hc: Hp thu tt qua ng ung, kh nng sinh hc 76-90%.
- Ch nh: Thng hn, vim mng no, nhim khun thn kinh trung ng, nhim
khun k kh (Vi khun khng cn O2), hoi th sinh hi, nhim khun mt v tai.
- Chng ch nh: Khng dng c iu tr cc nhim khun thng thng nh
cm lnh, cm...
- Khng thuc: Hin nay t l khng thuc cao vi vi khun khc nhau t 42-85%.
- Tai bin: Gy thiu mu=> gim hng cu, gy vim dy thn kinh. Do t dng,
ch dng trong trng hp c bit.
Sn xut chloramphenicol
- Vi nt v cu trc v ng phn: C 2 C* (C1 & C2) =>22 ng phn. ng phn c
hot tnh l D(-)-treo, D(+)-treo khng c hot tnh. 2 ng phn Erytro c c tnh
nn cn loi b.
- Sn xut chloramphenicol:
a. Sn xut bng ln men vi sinh vt vi Steptomyces venezuelae.

-74-

b. Sn xut bn tng hp ha hc
C nhiu patent cng b v sn xut chloramphenicol, sau y l mt s phng php
u vit trong s ang c s dng trong cng nghip:
- i t etylbezen
H2
C

HNO3/H2SO4

Br2

KMnO4/Al2(SO4)3

H2
C

O2N

CH3

O2N

CH3

CO

N4(CH2)6
O2N

Ac2O/CH3COONa

O2N

CH2Br

C
O

CH2NH2

C
O

Al(OiPr)3

CH2O/NaHCO 3

O2N

C
O

O2 N

CH2NHAc

H
C

O2N

C
O

CHNHAc
CH2OH

Meerwin-Poundorf

1. H2O/H+

CHNHAc

Cl2CHCOOC2H5

H
C

O2N

H
C

O2N

2. D-tartaric
tch dng phn

OH CH2OH

CH3

CHNH2

OH CH2OH
D(-)-treo-1-(p-nitrophenyl)2-amino-1,3-propan-diol

CHNH COCHCl2

OH CH2OH

chloramphenicol

- i t p-nitrotoluen
MnO2
O2 N

CH3

H2NCH2COOH

O2 N

H
C

O2 N

CHO

CH

NH
2

OH COOH

20-201

20-203
DL-treo--nitrophenyl-serin

20-202

LiAlH4

ROH/HCl

H
C

O2 N

CH

H
C

O2 N

NH2

OH COOR

tch dng phn

20-200
D(-)-treo-1-(p-nitrophenyl)2-amino-1,3-propan-diol

NH2

OH CH2OH

20-205

20-204

axit D-tactaric

CH

Cl2CHCOOC2H5

O2 N

H
C

CH

NHCOCHCl
2

OH CH2OH

20-194
chloramphenicol

* iu ch chloramphenicol-succinat (20-206)

-75-

H
C CH

O2N

NHCOCHCl2

H
C CH

O2N

OH CH2OH

O
20-207

20-149
chloramphenicol

NHCOCHCl2

OH CH2O COCH2CH2COO
H

O
NH2CH2CH2OH

HCOOH

H
C CH

O2N

NHCOCHCl2

(-) (+)

OH CH2O COCH2CH2COOH3NCH2CH2OH
20-208

H
C CH

O2N
20-206
Chloramphenicol

NHCOCHCl2

OH CH2O COCH2CH2COO
H

* Tng hp thiaphenicol (20-195)

CH3Cl

SH

NaOH

H
C CH

H3CS

CH3 COCl

H3CS

AlCl3

NHCOCHCl2

H3CS

CH3COOH
H3CO2S

H
C CH

OH CH2OH

Dng thuc v hm lng

- Vin nn v nang 0,25g chloramphenicol.
- L 1g chloramphenicol dng natri succinat.
- Thuc nh mt 5ml, 10ml 0,4%.
- Tup 5g m tra mt 1% chloramphenicol.
- M kem bi ngoi da 1%, 5%.
- Vin t m o 0,25g chloramphenicol.
e. Cc khng simh nhm Tetracyclin
* i nt v lch s ca nhm tetracylin
* Cc vi sinh vt sn sinh ra cc tetracylin
- Streptomyces aureofaciens (CTC, TC, DMCTC)
- S.rimosus (OTC, TC).
* Tnh cht ha hc ca nhm cc hp cht tetracylin
Bng 20.8 Cu trc ha hc ca cc khng sinh tetracylin
R4

R3
H

7
6

H3C
R2
H

CH3
N

4a
12a

OH

11

OH

5
5a

10

NHCOCHCl
2

OH CH2OH
20-195
Thiamamphenicol

R5

COCH3

12

OH

-76-

OH
O

CONHR1

Stt Tn
1 Chlortetracylin*(20-209)
(aureomycin, xathomycin, dibiomycin)
2 Oxytetracyclin*(20-210)
(tetramycin, sigmamycin, tetran)
3 Tetracyclin*(20-211)
(achromycin, sigmamycin, tetran)
4 Demeclocycline*(20-212)
(ledermycin, declomycin, meciclin)
5 Rollitetracyclin (20-213)
(Reverin, syntetrin, tetraverin)
6 Methacycline (20-214)
(rodomycin)
7 Doxycycline (20-215)
(vibramycin)
8 Minocycline (20-216)
(minocin)
9 Sancycline (20-217)
(bonomycin)
10 Meclocycline (20-218)
(Meclan, mecloderm, mechitin)
11 Lymecycline (20-219)
(armyl, tetralisal, tetramyl)
12 Pipacycline (20-220)
13 Nitrocycline
(nitrocyclinum)
14 Demecycline*
(Demecyclinum)
15 Bromtetracyclin
Ghi ch: * Cc tetracyclin t nhin
X= CH2NH-CH(COOH)-(CH2)NH2
Y=

H2CN

R1
H

R2
H

R3
OH

R4
CH3

R5
Cl

OH

OH

CH3

OH

CH3

OH

Cl

OH

CH3

OH

CH2 CH2

OH

CH3

N(CH3)2

OH

CH2 CH2

Cl

OH

CH3

Y
H

H
H

OH
H

CH3
H

H
NO2

OH

OH

CH3

Br

H2 CN

NCH2 CH2OH

* Lin quan cu trc v tc dng

cho mt phn t tetracylin c tc dng khng sinh cn phi c cc iu kin sau:
- Cn phi c h thng hai nhm cho mu (nh trong cng thc 20-222) hay phi c
h C-1,3 dixeton v C11-C12--xeton.
- Cc cu hnh ca cacbon C4, C4a, C5a, C12a tng ng nh cu trc khng gian
trong phn t 20-223 (quan h vng A/B l cis) 5a-h, c nhm bazo (nhm
dimetylamino) C-4 l

-77-

R
N

4a
12a

9
10

OH

11

OH

5
5a

12

OH

20-223

2
1

OH
O

- H xeto/enol C10-C12 l bt di bt dch.

- Cc nhm th trn cc v tr 5,6,7,8,9 c th thay i nhng nhng thay i cho
n nay vn cha thy lm tng hot lc hay m rng ph tc dng cc nhm th c
th: NO2, Cl (C-9), OH (C-7). Cc dn xut 6-desoxi (doxycyclin), nhng dn xut
6-hidroxi th hon ton mt tc dng.
- S thay i nhm th R1 trn N ca nhm carboxamit v tr C-2 khng lm thay
i hot tnh nhng ci thin tnh cht dc ng hc, tng tan trong nc ca hp
cht v cho dung dch bn vng hn.
* Cc yu t lm gim hot tnh:
- Nhm th Cl C-9, NH2 C-7.
- Khi thay i C-6 bng S (thia-tetracylin) th hp cht thn lipit hn, tng c tnh
khng khun nhng c cng cao nn khng dng c trong iu tr.
-pH>8 vong C ca mt s tetracyclin b ph hy, nhm th Cl C-7 thc y nhanh
s phn hy ny.
- Chelat gia tetracyclin vi cc kim loi a tr Men+ (n2).
- Cc n cht 4-desamino ch cn c tc dng rt yu tc dng chng li vi khun
gram m.
Sn xut cc tetracyclin t nhin (sinh tng hp)
Sn xut cc tetracyclin t nhin c tin hnh trong hai giai on:
a. Giai on ln men hot cht:
Cc yu t quan trng ca giai on ny l ging, mi trng v ch l men. Mi
loi tetracyclin do mt chng tng ng sn sinh ra, v d chlortetracyclin th do
chng S.aureofaciens, oxitetracyclin th do chng S. rimosus, tetracyclin th do chng
S.virudifaciens...(xem bng 20-9). Chng phi c t bin, chn lc nui dng
c chng tt. Mi nh my sn xut c cht lng chng mt khc.
- Thnh phn mi trng ln men chlortetracyclin gm (%): bt ng 6; cao ng 0,5;
amoniunfat 0,5; canxicacbonat 0,5; canxicacbonat 0,5; coban clorua 6H2O 0,001;
CaCO3 0,5.
- Thnh phn mi trng ln men tetracyclin gm (%): bt ng 6; cao ng 0,5; NaBr
0,2; benzylthiocianua 0,0001; 2-mercaptobenzothiazol 0,001, CaCO3 0,5.
- Thnh phn mi trng ln men oxytetracyclin gm (%): bt ng 6; cao ng 0,5;
amoniunfat 0,6; CaCO3 0,6; CoCl2.6H2O 0,001.
b. Giai on chit sut, phn lp tinh ch.
Trong cng nghip sn xut cc tetracyclin chit sut , phn lp hot cht ngi ta
thng s dng phng php sau: Chit bng dung mi hu c, bng kt t v trao
i ion. C lc kt hp cc phng php ny. V d chit sut phn lp tetracyclin
hidroclorit ngi ta thc hin nh sau: Dch ln men sau khi lc ngi ta iu chnh
v pH= 8,5 kt ta tetracyclin bazo bng n-butanol. Lc dch butanol vi dung mi
khng phn cc kt ta ly tetracyclin. Ha tan ta vo axeton v dng dung dch
-78-

HCl iu chnh v pH=6, ta tetracyclin hydroclorit to ra c lc v kt tinh li

nhiu ln trong methanol hoc n-propanol n lc t cht lng tetracyclin
hidroclorit dc dng.
Tetracyclin t nhin bn cnh s dng lm thuc cha bnh cho ngi cn c s
dng trong th y v c bit s dng kh nhiu lm cht tng trng tht v trng.
* Cc tetracylin bn tng hp
- Tng hp rollitetracyline (20-213), lymecyline (20-219) v pipacycline (20-220)
H3C

R3
H

H3C
R2
H

CH3
H3C
OH

R3
H

H3C
R2
H

CH3
OH

CH2O
amin

NH2
X
OH
OH

OH

OH
O

OH

OH

20-210
tetracyline

X
20-213
rollitetracyline (135)
20-220
pipacycline (136)

N
N

N CH2CH2OH

20-225

COOH
HN C (CH2)4 NHAc
H

20-219
lymecycline (137)

COOH
HN C (CH2)4 NH2
H

- Tng hp methacycline (20-214) v doxycycline (20-215), methacycline da

doxycyline c tng hp bng con ng ging nhau, u xut pht t
oxitetracycline 20-210 (138)

-79-

H3C
CH3
N
R3 OH
H
H
OH

H3C

H3C
CH3
N
R3 OH
H
H
OH

H3C

NH2
OH

OH

OH

NH2

OH

OH

6---deoxy-OTC

20-210
OTC

H3C

H3C
CH3
OH
N
H
OH

N-clo-succinimid

Cl

OH

H+,H2SO4

NH2
OH

O Cl

OH

H2F2 (closunfonic

20-226
11-clo-oxi-tetracycline

CH2

H3C
CH3
OH
N
H
OH

CH2

H3C
CH3
OH
N
H
OH

Zn/HCl, NaHCO3 (Metanol 50%)

NH2
OH

O Cl

OH

NH2

Na2S2O4

OH

OH

OH

20-214
Methacycline

20-227
11-clo-6-metylen-oxitetracyclin

T hp cht methacyclinec(20-214) vi 2 phn ng sau i ti c doxycycline (20215) (139).

- Tng hp docycycline (20-215)
S
H3C
CH3
CH2 OH N
H
H
OH

C6H5
H3C

R-SH

OH
H

CH3
OH

OH

NH

NH2 Pd,Ni

NH2
OH
OH O
O
20-214
Methacycline

H3C
CH3
N
CH3 OH
H
H
OH

OH

OH
OH O

20-228
13-phenylmercapto-oxitetracycline

- Tng hp minocycline (20-216):

-80-

OH

OH
OH O
20-215
doxycyline

OH
H

H3 C
H

CH3

H3 C
H

Khu ha

OH

CH3

NH2
OH

OH
OH O

NH2
OH

20-229
demecycline
(6-demetyl-tetracycline

KNO3/H2F2

OH

OH
OH O

20-230
(6-demetyl-6-deoxi-tetracycline)

NO2

NO2
+

OH
20-231
7-Nitro

NO2

H2N

ON2
OH

OH

20-232
9-nitro

20-233

H2N
OH
20-234

H3 C

NO2

CH3
N

H2/Pd
+

H3 C
H

CH3
OH

CH2O
carbamid

N2
OH
20-235

OH
H

OH
20-236

NH2
OH

OH
OH O

20-216
minocycline

Hnh 20-17. S tng hp minocycline (20-216) t demecycline.

f. Cc khng sinh nhm aminoglycozid (141-146)
* M u v i nt v lch s ca nhm khng sinh aminoglycozid
- Khng sinh u tin l Streptomycin do Wasksman (1944) tm ra, sau l
neomycin (1949), Kanamycin.
- Aminoglycosia = aminosid = amino cyclitol.
- L nhm khng sinh quan trng trong vic iu tr cc bnh nhim trng trm trng
do gram (-).
* Cc vi sinh vt sn sinh ra aminoglycozid
Bng 20-10. Cc khng sinh aminoglycozid quan trng s dng trong thc t
Tn khng sinh
Nm
Vi sinh vt sn sinh ra
Tc dng
phn lp
Streptomycin
1944
Steptomyces (S) griseus
G+, G-, Mycob
Neomycin
1949
S.fradiae
G+, G-, Mycob
Kanamycin A
1958
S.kanamycetius
G+, G-, Mycob
Paramomycin
1958
S. rimosus f.paramoycinus
G+, G-, ng
vt n bo.
Hygromycin B
1958
S.hygroscopicus
K sinh trng,
thuc th y.
Stectinomycin
1961
S.spectabilis,
Cc lu cu
Gentamycin C
1963
S.flavopersicus
khun
Micromonospora (Mic)
G+, G-

-81-

Kasugamycin
Destomycin
Validamycin
Kanamycin B

1965
1965
1967
1969

Tobramycin
(nebramycin-6)
Sisomycin
Ribostamycin
Lividomycin
Micronomicin
Apramycin

1969

Astromycin

1976

1971
1970
1971
1974
1974

Purpurea. Mic.echinospora
S.kasugaenis
S.rimofaciens
S.hygroscopicus
var.limonensis
S.kanamyceticus,
Tenebrarius
S.tenebrarius
Mic.inyoensis
S.ribosidificus
S.lividus
Mic. Sagamiensi
S.tenebraius

Bo v thc vt
K cu trng
Bo v thc vt
G+, GG+, GG+, GG+, GG+, GG+, GThuc th y,
thc n gia sc
G+, G-

Mic.Olivoasterospora
Cc aminoglucosid tng hp
Dhydrosteptomycin 1974
G-, Mycob
Amikacin
1973
G+, GDibekacin
1975
G+, GMetilmycin
1976
G+, GHabekacin
1981
G+, GMycob: mycobaeterium.
* Cu trc v tnh cht ha hc ca cc khng sinh aminoglycozid
Cu trc ha hc ca cc aminoglycozid
a. Phn aglucon hay genin l cc hp cht cha vng cyclitol (poliancol vng) trong
c 2 nhm OH v tr C-1, C-3 (1,3) hoc C-1, C-4 (1,4) c thay bng 2 nhm
amino (-NH2) hoc guanidine (- HNC(NH)NH2). Cc aminoglycozid cng c phn
nhm trn c s cu trc ca aglucon (ca cyclitol). Phn nhm tip na c th theo
s phn ng/aminoglycozid, cht lng ca n v v tr gn kt ca n vi aglucon.
Aglucon (cyclitol) c th l dn xut ca 1,3-diamino-(streptidin (I), streptamin (II),
2-deoxistreptamin
(III)(DOS),
1,4-diamino-(fortamin(IV)),
monoamino(validamin)(V) hoc khng c cha nhm amino (inositol) (VI) ca cyclitol. Sau y
l mt s cu trc mt s agluco chnh ca cc aminoglycosid (Hnh 20-18).

-82-

R3

R2 NH

R2

R3

NH

HN R1

R4

OH

HO
H
N

HO

OH

OH

OH

R1

Streptidin (I)
Streptamin (II)
2-Deoxistreptamin (DOS) (III)
HO

HOH2C

OH

OH

HO

OH

OH

NH2
HO

HO

HO
OH

OH

OH

HN CH3
OCH3

OH

OH

Fortamin (IV)

L-(+)-inositol (VI)

Validamin (V)

Hnh 20.18: Cc cu trc aglucon ch yu ca cc khng sinh nhm aminoglucozid

b. Phn ng: Gm cc ng c amin hoc khng c amin 6 hoc 5 cnh. Sau y
l cu trc ca mt s thnh phn ng ch yu. (Xem hnh 20-19).
HOH2C

HOH2C

H2NH2C

HO

HO
HO

HO
HO

NH2

D-glucosamin 2

HO
OH

OH

D-glucosamin 3

NH2

OH

Neosamin C

O
H

CH3

HO
H3 C

CH
O

H2 N

H3 C
H2 N
OH

NH2

OH

Garosamin
O

H3 C

Purpurosamin

OH

HOH2C

CH2NH2

HO

OH

Sirosamin

OH

CHO

OH

OH

OH

OH

D-Riboz

L-Streptoz

Hnh 20.19: Cc cu trc ng ch yu ca cc khng sinh nhm aminoglucosid

* Phn nhm cc khng sinh aminoglycozid
Vic chia nhm cc khng sinh aminoglycozid quan trng theo phn cyclitol (phn
aglucon) c th thy trong cc phn nhm sau:
- Cc khng sinh ca Steptidin (I) c Steptomicin (20-237)
- Cc khng snh ca Steptamin (II) co Spectinomycin (20-238)
- Cc khng sinh ca 2-deoxistreptamin (III) theo v tr gn kt ca n vi phn ng
c cc nhm sau:
+ Nhm dn xut th v tr 4,5 bao gm: neomycin (20-239), paramomycin
(20-240), lividomycin (20-241) v ribostamycin (20-242).

-83-

+ Nhm dn xut th v tr 6,4 gm c: kanamycin A (20-243), kanamycin B

(20-244), tobrramycin (20-245), dibecacin (20-246), amincacin (20-247), gentamycin
C1 (20-248), gentamycin C2 (20-249), gentamycin C20 (20-250), sagamycin (20-251),
sisomycin (20-252), netimycin (20-253).
+ Nhm cc dn xut c mt nhm th v tr C-5 gm c hygromycin B (20254), destomycin B (20-255).
+ Nhm dn xut c mt nhm th C-4 c apramycin (20-256)
Cc khng sinh khung fortamin (IV) c fortimycin (20-257).
Khng sinh nhm validamin (V) (monocyclitol) c validamycin A (20-258).
Khng sinh nhm cyclitol trung tnh (L-(+)-inositol (VI)) c kasugamycin
(20-259).
Cu trc cc khng sinh ch yu ca nhm aminoglycozid c th thy trong hnh
20.20
OH

H2N

H
H3C N

NH

CH3

HN
HO

H
N

HO
NH

NH2
H3C NH

NH

OHC

CH2OH

H
H3C N

20-237 OH
streptomicin

R2

H2C

HO

NH2

NH2

HOH2C

OH

CH3

HO

H2N
O

H2N
O
O

HO

NH2

NH2
HOH2C

O
HO

O
20-238
spectinomycin

HO

OH

O
CH3

OH

R1
H2C

OH O

CH3
OH
HOHC

CH3
OH

HO

NH2 O OH
H2N CH2
R1
neomycin (20-239)
NH2
paronomycin (20-240) OH
lividomycin (20-241) OH

OH OH

R2
OH
OH
H

-84-

OH
20-241
ribostamycin

NH2

HOH2C
HO
H2N

R2

R1

R3
H2
C NH2

HO

OH

O
R4

NH2

N
H

Kanamycin A (20-243)
Kanamycin B (20-244)
Tobramycin (20-245)
Dibekacin
(20-246)
Amikacin
(20-247)

R1
-OH
-NH2
-NH2
-NH2
-NH2
-OH

R2
R3
R4
-OH -OH -H
-OH -OH -H
-H
-OH -H
-H
-H
-H
-H
-H
-H
-OH -OH -COCH(OH)CH2CH2NH2

OH
H3C
H3CHN

H2N

R1

HO

OH
O
H2N

C
O

HN

NH2

R1
Gentamicin C1 (20-248) -CH3
Gentamicin C2 (20-249) -CH3
Gentamicin C10 (20-250) -H
Sagamicin
(20-251) -H

-85-

R2
-CH3
-H
-H
-CH3

H
R2

OH
O

H3C
H3C
NH

H2N

H2
C NH2

O
OH

HO
O

O
R

NH2

N
H

Sisomicin (20-252), R: -H
Netilmicin(20-253), R: -C2H5
CH3
OH

HO

NH2

OH

NH2
O

H2
C OH
OH
H
N R2

O
HO
N
H

H2N
HO

NH2
HO
OH

Hygromycin B (20-254) R1:-H, R2:CH3

Destomycin A (20-255) R1:-CH3, R2:-H
H2C

H3C
H2NH2C

OH
O
OH H3CHN
O
O

O
H3CO
20-257
Fortimicin

OH
O

20-256
apramycin

H2C

NH2

CH2OH

HO
O

R1

NH2

OH

HO

OH

NH2
NH2

HO
HO

COOH

OH
HN

HO

H3C

O
N
H

H2N

OH
HO

CH2

OH

HO

O
HO

OH

HO

20-258
Validamycin A

H2
C OH

20-259
Kasugamycin

OH

OH
OH

Hnh 20.20: Cc khng sinh ch yu ca nhm aminoglycozid (tip theo)

* Tnh cht sinh hc v lm sng ca cc khng sinh aminoglycozid
Hu nh tt c cc khng sinh aminoglycozid u c hot ph rng. u c tc dng
chng li vi khun G(+),G(-) v cc vi khun chu axit (Mycobacteriales). Ph tc
dng ca chng duy nht ch c mt thiu st l khng mnh chng li cc vi
-86-

khun k kh clostridia, Peptococcus...v cc loi khc nhau ca Streptococcus. Mt s

aminoglycozid (higromycin B, destomycin) c hiu lc chng li cc k sinh trng
ng vt n bo v su b, ni bt l paronomycin trong phm vi lm sng c th s
dng chng li ng vt n bo. Validamycin v kasugamycin bn cnh tc dng
khng khun chng cn c hiu lc ti cc loi nm gy hai cy trng.
u vit ln nht ca cc aminoglycozid l tc dng tuyt vi vi cc trng hp bnh
do vi khun loi G(-) gy ra, m trc ht l trong cc ly nhim do Pseudomonas,
Proteus v Klebsiella. Tc dng ca chng (tr spectimomycin v kasugamycin) l
dit khun. Trong qu trnh s dng thng xut hin khng thuc, c bit trong cc
trng hp s dng di ngy. C ch hnh thnh khng thuc c xc nh l
trong qu trnh dng thuc cc vi khun khng li bng cch sn xut ra cc enzim bt
hot (cc enzim phosphory ha, axetyl ha, adenyl ha...).
Khng c bt k mt aminoglycozit no c kh nng hp th qua ng tiu ha ( qua
mng rut) do ch c th s dng qua ng tim. Cc tc dng ph cyar cc
khng sinh nhm aminoglycozid thng l gy c thn v tc hi n thnh gic
(ototocic). Trong lm sn thng c s dng di dng tim bp, thuc hp thu rt
tt, t nng thuc trong mu ti a l 30-90 pht, thi gian bn hy (t1/2) ca
thuc 2-3 gi. Trong cc trng hp nguy kch khuyn co nn tim ven.
Thuc o thi nhanh trong thi gian 12-24 gi v hu nh i qua thn di dng
nguyn vn, phn nh ti hp thu qua cc ng ln v c lm m c li trong
thn v v th cng l nguyn nhn gy c cho thn. Mt tc dng ng quan tm
khc l gy ri lon cn bng chc nng nghe. Tc dng ph ny s ht khi thi khng
dng thuc. Cc khng sinh aminoglycozid cng c th c c tnh thn kinh.
Cc thuc ch yu: Gentamycin, Streptomycin, Neomycin, Kanamycin,
Paramomycin, Spectinomycin, Tobramycin, Sisomycin, Amikacin, Netilmycin,
Kasugamycin v Validamycin.
* SN XUT CC AMINOGLYCOSID ( SINH TNG HP )
- Cc KS aminoglycosid ch yu c sn xut ra bng con ng ln men (
tng hp c hu ht cc KS loi ny bng con ng ho hc nhng cha sn xut
c quy m cng nghip )
- Thnh phn ch yu xy dng ln khng sinh aminoglycosid l : phn cyclitol,
phn aminoglucoz/glucoz
Cng nghip ln men sn xut cc khng sinh aminoglycosid yu cu n oxy,
thc hin nhit 28-30 0 C, trong thi gian 4-7 ngy. Th tch cc thng ln men
khong 50-150 m3. S dng glucoz, tinh bt hoc dextran lm ngun cung cp
cacbon. Trong tng trng hp c cho thm cc nguyn t vi lng ( v d sn xut
gentamycin cn cho thm ion Co3+. Lng khng sinh thng t c 10004000mg/1lt ( trng hp steptomycin, kasugamycin, validamycin cn cao hn mac
ny ).
Thng trong ln men mi mt cht th bn cnh thnh phn sn phm chnh cn
to ra cc sn phm ph. Thng l nhng cht hm lng khng nhiu, nhng li c
cu trc, nhm chc gn ging nhau nn vic tch phn lp l vn cn phi quan
tm.
Ngy nay vic phn lp cc aminoglycosid hu nh ch s dng phng php trao
i ion. T dch ln men cc khng sinh mang tnh baz mnh bn vng trong kim,

-87-

c hp ph qua nha trao i cation baz yu ( Amberlite, IRC-50, BioRex-70,

Varion-KCG ) gi tr pH trung bnh, sau vi dung dch amoni hidroxi, bng k
thut ra gii chn lc thu hn hp hot cht. Tip tc tinh ch, phn lp hoc tch
loi sn phm ph bng s dng sc k trao i ion.
Sau y l mt v d v sn xut streptomycin.
Bao t Streptomycesgriseus gi trong ct c sy sang thch nghing ri chuyn
sang bnh lc to bnh ging [mi trng nhn ging (%) : cao men bia (0,5); glucoz
(3); amoni sunfat (0,3); CaCO3 (0,6); KH2PO4 (0,02); NaCl (0,25) pH = 7 ]
Cy ging vo ni cp 1 27 0C, c thng kh, khi khun ty th ln th chuyn
sang ni cp 2, nhn ging thm khong 40 gi. Sau chuyn sang ni ln men.
Duy tr cc thng s: nhit ln men 27 0C, thng kh 0,5 l/pht/lt; pH mi trng =
8; thi gian 95-100h ( n khi hm lng khang sinh khng tng) chuyn khi dch
ln men sang ni m, thm nc mm v dinatri photphat ta ion canxi, lc. Dch
lc iu chnh v pH = 7 v cho i qua ct trao i c cha nha cacboxylic (
Amberlite IRC 50 ) n khi nha bo ho streptomycin th ra ct bng HCl hoc
H2SO4 1N.
Dch phn ng hp ph c ty mu bng than hot, lc. Dch lc li cho i qua
ct trao i cationit ( KY-2-20) loi b mui kh mu bng than hot. Lc, thu
c dch lc cha streptomycin. Dch lc ny c ct chn khng ( lin tc) c
c. Axit ho dch c c vi H2SO4 to mui, thm than hot, kh mu. Lc, dch
lc c lc qua mng lc sinh hc loi ch nhit t v v trng ho. Dch lc c
nn vo my sy phun to bt kh streptomycin sunphat. ng l trong phng v
trng.
g. CC KHNG SINH MACROLID
* M U V I NT V LCH S CA NHM KHNG SINH MACROLID
Khng sinh macrolid u tin c pht minh nm 1950 l picromycin, k sau
l vo nm 1952 li tm ra erythomycin mt khng sinh macrolid quen bit nht v
quan trng nht ngy nay. Bit rng, cho n nay trong ngha hp ca khng sinh
macrolid ngi ta tm thy trn 200 hp cht.Cc khng sinh loi ny ch yu tc
dng trn gram (+).
c trng ho hc cc khng sinh macrolid l c mt vng lactam ln ( 12 n 17
cnh ), thng l 12, 14, 15 hoc 16 nguyn t), trn i vng lacton ny c phn
nhnh, vi a nhm chc, c gn kt vi cu trc c bit ca ng trung tnh
(glucoz ) hoc ng amin (aminoglucoz) bng lin kt glucosidic.
- Lit k vo nhm ny cn c polien-macrolid (Nystatin) c s cnh ca i
vng khong 24-44, monolacton, dilacton c s cnh i vng 8-52,
macrotetralid.
- Khng sinh quan trng nht trong nhm l erythromycin
* CC VI SINH VT SN XUT RA CC MACROLID.
Cc khng sinh macrolid ch c cc chng thuc Actnomyces, nh Streptomyces,
streptoverticillium v Micromonospora sn sinh ra. Phn ln cc macrolid c to ra
vi phc gm nhiu (3-10) thnh phn. Cc khng sinh macrolid quan trng nht ang
c s dng trong thc t, nm tm ra chng, chng vi sinh vt sn sinh ra khng
sinh c tng kt li trong bng 20-11.
Bng 20.11. Cc macrolid t nhin s dng trong thc t nm v chng sinh vt
sn sinh ra chng.

-88-

Tn khng sinh
Erythromycin
(A)
Carbomycin
Leucomycin
Spiramycin
Oleandomycin
Tylosin

Nm
ch
1952
1952
1953
1954
1955
1961

iu Chng vi sinh vt sn sinh ra

Tc dng

S. erythraeus, S. griseoplanus

G+

S.halstedi
Streptovericillium
kitasatoensis
S. ambofaciens
S. antibioticus
S. fradiae

G+
G+

G+
G+
G +, Th.T.Y,T.A,
My
narbonensisor. G +, T.A

Josamycin
1967
S.
(Leucomycin A3 )
Josemyceticus
Midecamycin** 1971
S. mycarofaciens
G+
Maridomycin** 1973
S. hygroscopicius
G+
Roasarammycin 1973
Mic. Rosaria
G+
Ivermectin
1978
S. avermitilis
K, Th, T, Y
Ghi ch ( ca Bng 20.11)
* Cc thuc khng cn trn th trng
** ch c dng dn xut axyl ho ( axetyl, propionyl); G+: Gram dng; T>A
thc n gia sc Th.T.Y : Thuc th y, My: micoplasma; K: k sinh trng.
* CC TNH CHT HO HC CA CC KHNG SINH MACROLID
. c tnh l, ho tnh
- L nhng hp cht thn m, v ng, ho tan c trong dung mi hu c.
- Do c phn ng amin nn c tnh baz, d tan trong axit nhng khng bn trong
axit.
- Phn t lng t 500-900, vng lacton d thu phn trong mi trng qua kim
hay qu axit.
. Cu trc:
Cc macrolid bao gm hai phn: aglucon ( hoc genin) v phn ng.
Phn aglucon l vng lacton ln gm 12 n 16 nguyn t to thnh vng 12
n 16 cnh, cc nhm th trn vng c th oxo, hydroxyl, metoxy, ankyl ( ch yu l
metyl) formyl-metyl ni i v ni i lin hp. Nhm th formyl- metyl c trng
cho cc macrolit c vng 16 nguyn t (16 cnh), cc nhm hydroxyl trong cc phn
t cc hp cht thin nhin thng c axyl ho ( vi cc nhm axetyl,
izopropanoyl, isobutanoyl, n-axyl...).
Phn ng: gm cc ng trung tnh (glucoz) v ng amin (
aminoglucoz). Cc ng amin a li tnh baz cho phn t macrolid, cc ng bao
gm : desosamin, cladinoz, Oleandroz, mycaroz, forosamin, mycaminoz.
Phn nhm: Cn c vo s nguyn t ca vng ln lacton phn nhm:
Vy c nhm vng 12, 14, 15, 16. Mt s macrolid quan trng trong nhm c th thy
trong bng 20-12. Ch rt t khng sinh macrolid t nhin thuc nhm 12 hay 15 cnh
cn li i b phn l loi ( c trn 100 hp cht ).

-89-

CC KHNG SINH MACROLID BN TNG HP

Cc khng sinh macrolid bn tng hp c iu ch i t mt s macrolid t
nhin bng cch bin i mt s nhm th t c mc tiu l khc phc nhng
nhc im ca cht khng sinh gc v d t erythromycin A, khi thay i mt s
nhm th to ra cc cht bn tng hp bn hn vi axit d dy, m rng ph tc dng
v ci thin tnh cht dc ng hc:
Thay nhm oxo bng oxim th thu c roxythromycin (20-272).
Thay nhm OH C-7 bng nhm metoxy ( OCH3 ), c clarithromycin (20-273)
M rng vng lacton ra thnh vng 15 nguyn t (c cha mt nguyn t nit ),
thay C=O v tr 10 bng nhm -N-(CH3)CH2 th thu c azithromycin (20-274).
Thay CH3 C-9 bng flo thu c flurithromycin (20-275) bn vi axit.
Cng thc
R

Erythromycin A (20-261) -OH -CH3

Roxythromycin (20-272) -OH -CH3
Clarithromycin (20-273)
-OCH3 - CH3
Flurithromycin (20-275)
-OH
-F
Azithromycin (20-274)
-OH
-CH3
Dirithromycin (20-276)
-OH
-CH3

R
cng thc

* CC C TNH SINH HC V LM SNG CA CC MACROLID

Ph tc dng :
- Cc khng sinh macrolid c ph tc dng tng i hp, nhy cm vi cc vi
khun
- Gram dng: T cu, ph cu, lin cu, trc khun than, bch cu.
- Gram m: Lu cu, mng no cu.
- Trn mt s vi khun khc: Mycoplasma, Rickettsiae, Chlamydiae...
- Khng nhy cm vi phn ln vi khun Gram m, nht l cc vi khun gy
bnh ng rut do khng sinh kh vt qua mng t bo vi khun v ni bo.
Tc dng ph : Cc khng sinh macrolid t c, dung np tt v t c tc dng ph
(5-15%). Tc dng ph bin nht l vn tiu ho ( au bng, nn ma, a chy), c
bit l dng liu cao v kch ng ti ch. trnh iu ny lc tim cn truyn
chm... Tc dng ph t gp l: ln my ay, tai ic ( c phc hi).
Dc ng hc:
Cc khng sinh macrolid hp thu tt ng tiu ho; vo c th phn b mi t
chc, nhng tp trung cao hn cc m ni tng ( gan, phi, thn ), hnh nhn, tuyn
tin lit, xng, rng, o thi yu qua ng gan, mt.
Vi cc c tnh trn, cc khng sinh macrolid ch ung iu tr cc nhim khun
do vi khun tp trung cao.
Ch nh: Cc khng sinh macrolid c tc dng tng i ging nhau m trong cc
khng sinh macrolid th erythromycin l quan trng nht. Erythromycin dng iu
tr cc bnh nhim khun nh vim ph qun, vim rut do Campylobacter, h cm,
bch hu, vim phi v cc nhim khun do Legionella, vim kt mc tr s sinh v
vim kt mc do chlamidia ho g, vim phi, ( do Mycoplasma, Chlamydia, cc loi

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vim phi in hnh v c Streptococus, vim xoang, phi hp vi neuomycin

phng nhim khun khi tin hnh phu thut rut.
Erythromycin c th dng cho cc ngi bnh b d ng vi cc khng sinh lactam v nn dnh ring cho ngi bnh d ng vi penicillin. C th dng thay th
cho penicillin trong d phng di hn thp khp cp.
Phm vi s dng ca mt s khng sinh macrolid khc nhau:
Trong iu tr cho ngi th erythromycin l khng sinh macrolid quan trng nht.
Mi nm ch cn sn xut mt tn.
Spiramycin ch yu ch gii hn dng cho th y. Cn s dng cho ngi mt s
nc chu u v cc nc Nam M b hn ch.
Cc khng sinh macrolid mi nht nh midecamycin, maridomycin th ngha s
dng ca chng cn cha c xc nh mt cch chc chn, cc thuc ny ch mi s
dng mt s nc.
Tylosin th ch s dng cho th y, iu tr cc bnh ng h hp gy ra g v
ln bi Mycoplasma, cng nh s dng trong sn xut thc n gia sc, gia cm vi
mc ch tng trng ( c phi trn 100g/1 tn thc n). Ngoi ra tylosin cn c s
dng bo qun thc phm.
Cc khng sinh macrolid bn tng hp c iu ch ra vi mc ch lm tng bn
vng, ci thin mi v, ci thin v tnh cht dc ng hc ( hp thu tt hn, tc dng
di hn, m bo nng cao trong mu...vv). Cc dn xut iu ch ra ch yu bng
phn ng axyl ha nh to stearat, lactobionat, succinat, hoc axetat, propionat...vv.
Hp cht khng sinh macrolid bn tng hp na l roxithromycin, l dn xut oxim
ca erythromycin, c nhiu c tnh u vit, ang c nhiu ha hn trong iu tr.
* C CH TC DNG, LIN QUAN CU TRC-TC DNG
* C ch tc dng:
- Ngn cn sinh tng hp protein
- Ngn cn gn kt ca tRNA - ngn cn mc xch peptid.
* Lin quan cu trc tc dng
- Phn t c tc dng nu cha c hai thnh phn ( aglucon ln thnh phn ng
hoc amino-ng.
- Vi cc macrolid c vng 14 th khi este ho nhm OH, hidrazon ho, oxim ho
khng lm thay i tnh cht tc dng.
- Nhm dimetylamino l iu kin tin quyt cho tc dng khng sinh
* SN XUT ( SINH TNG HP )
- Chng vi sinh vt sinh tng hp erythromycin l S. erythraeus
- i vng c xy dng t : axetat, propionate, butyrate hoc glucolat gn vi nhau
theo kiu u ui
- Thnh phn ng: t gluco, N-metyl, C-metyl ca nhm methiomin
- Thnh phn mi trng: tinh bt, bt u nnh, mui amoni.
- Nhit ln men 25-280C
- pH = 8-9
- X l tinh ch; Lc; chit vi etyl, butyl axetat.
- Tinh ch qua ct.
* Cc khng sinh macrolid chnh
- Erythromycin
- Oleandomycin

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- Spiramycin
* Cc khng sinh bn tng hp chnh
- Mydecamycin
- Josamycin
- Azithromycin
- Clarithoromycin
h. KHNG SINH LINCOSAMID
Trong nhm ny c lincosamid ( 20-279), y l khng sinh t nhin c phn
lp ra t mi trng nui cy Streptomyces linconensis vo nm 1962 v clindamycin
( 20-280) l ch phm bn tng hp i t licomycin. Cc khng sinh nhm lincosamid
c ph tc dng v c ch tc dng rt ging cc khng sinh macrolid ( erythromycin,
oleandomycin ) nhng cu trc li khc hn.
Tnh cht ho l ca cc khng sinh lincosamid:
- C phn ng nn dng t do tan trong nc
- Khng hp th UV nn nh lng bng sc k lng ( HPLC)
Ph tc dng
Tng t khng sinh macrolid c v ph v c ch tc dng nhng cc licosamid
c mt s c im ring:
- Rt nhy cm vi Haemophilus; nhy cm vi Clostridium perfringens nhng
khng nhy cm vi chng vi khun rut Clostridium difficile, loi c c t
gy vim rut kt mng gi.
- Nhy cm vi vi khun ym kh ni chung, loi c ngun gc rut v sinh dc
ni ring nn thun li khi dng lincosamid iu tr nhim khun vng bng
v vng chu.
- Stapphylococcus aureus nhy cm v t khng li cc khng sinh lincosamid,
iu ny to thun li khi cn thay th khng sinh -lactam trong iu tr.
- Clandamycin cn nhy cm vi mt vi dng k sinh trng st rt.
- Khng nhy cm vi Neisseria v Strrep.faccalis.
S khng ca vi khun
- C s khng cho axit gia lincomycin vi cc khng sinh macrolid
Tc dng khng mong mun
- Vim rut kt do c 1 s chng vi khun khng chu tc dng ca lincomycin
sn xut ra c t nng cao gy vim.
Tnh cht dc ng hc
- Hp thu tt ng rut, o thi qua mt- rut 60%
Cc ch phm i din
- Lincomycin.HCl l 0,5g x 2 ln / ngy ( tim bp )
- Clindamycin phosphate este. Ung hoc tim bp, tnh mch 0,6 - 2,7 g/ ngy
i. KHNG SINH POLYPEPTID ( A PEPTID)
L cc cht c cu trc peptid, c tc dng khng khun, c chit sut t mi
trng nui cy mt s chung ca Strreptomycin v Bacillus. Hin dng trong iu
tr c cc cht polymucin B, colistin, grammicin, tyrothridin v bacitracin.
k. POLYMYCIN B SUBFAT
Polymycin B c chit sut ra t mi trng nui cy Bacillus polymyxa vi
thnh phn gm polymycin B1, B2.

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Polymycin B1, B2 l N-monoaxyl-ecapeptid gm vng peptid 7-axit amin ni

vi mch nhnh cng l mt peptid 3 aminoaxit c kt thc bng gc N-axyl
(OC-R).
Sn phm dc dng l hn hp ca polymycin B1 + B2 dng mui sunfat.
-NH2
-NH2

-NH2

-NH2

Dbu - Thr - Dbu - COR

-NH2

Dbu - Dbu - Thr - Dbu - Dbu - D-Phe - D- Leu

(Dbu = axit , - diaminobutyric)

Polymyxin B1 (20-281), R-CO: (+)- 6- methyloctanoyl
Polymyxin B2 (20-282), R-CO: 6 - methylheptanoyl
Sn xut :
Nui cy Bacillus polymyxa trong mi trng v nhit thch hp
Lc ly dch ln men, thm ph gia to phc kt ta vi polymyxin, lc thu cn
v ra bng nc.
Ha cn vo dung dch mui sunfat ca mt amin bo mch thng, ngn trong
ancol: polymycin B sunfat c to ra, lc tinh th, kt tinh li thu sn phm l hn
hp polymycin B1, B2, bt trng ng, rt tan trong nc, t tan trong cn.
Ph tc dng :
Hu nh khng c tc dng trn vi khun Gram (+), trn vi khun Gram (-): nhy
cm vi Aerobacter, E. coli, Haemophillus, Klebsiella, Shigella, hu ht Vibro v
Yesinia.
Ch nh :
Thay th cc khng sinh cng ph tc dng khi cc khng sinh ny khng cn hiu
qu, trong cc trng hp vim no, vim ng tit niu, nhim trng mu do vi
khun Gram (-), nhy cm vi polymycin B.
Liu dng :
Ngi ln, tr em tim 3 mg/kg/24h, chia 4 ln.
Dng ngoi : Thng dng phi hp vi neomycin, gramicidin iu tr nhim
khun da, c bit do trc khun m xanh, dng thuc m 0,05 - 0,1 %.
c tnh:
- Suy thn
- Thn kinh : d cm chn tay v vng quanh ming, chng mt, trng thi kch
thch, mt phng hng, gim lc c, mt phn x gn.
- Suy h hp: lit h hp do c ch thn kinh c.
l. COLISTIN SUNFAT
Ngun gc:
Colistin c ly t mi trng nui cy Bacillus Colistinum phn lp t t ca Nht
Bn. Hin nay vn sn xut colistin ln men loi chng ny.
Cu trc:
Colistin c cu trc gn ging vi polymycin nhng th t cc axit amin c khc

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Colistin A, B ( hay cn gi l Polymycin E1, E2) l bt mn mu nh vng, khng

mi, bn trong khng kh v pH axit khng bn pH kim. D tan trong nc, khng
tan trong axeton, ete.
-NH2
-NH2
-NH2
L-Dbu

-NH2
-

L-Dbu

L-Dbu - Thr - L-Dbu - COR

-NH2
- Thr - L-Dbu - L-Dbu - D-Leu - D-Leu

( Dbu = axit , - diaminobutyric)

Colistin A (20-284), R-CO: (+) - 6 - methylloctanoyl (Polymyxin E1)
Colistin B (20-285), R-CO: 6 - methylheptanoyl (Polymyxin E2)
Ph tc dng :
Ph tc dng tng t polymycin B nhng hiu lc thp hn, khng tc dng vi
Klebciella pneumonia, Seratia marcessceus, E .coli v Shigella. Dng trong iu tr
cc nhim khun ngy cm, dng ngoi dung dch 0,3 % iu tr nhim khun tai
ngoi; thng phi hp vi neomycin.
Thuc t b vi khun khng; c tnh nh polymyxin B, ch c vi thn nht l
s dng cho tr em.
Ch nh:
Ch s dng khi khng dng c cc thuc khc trong cc iu tr sau:
- iu tr nhim khun ng tiu ha
- Nhim khun nng do vi khun Gram (-), nhim khun huyt, vim mng no,
nhim khun thn, nhim khun ng niu-sinh dc do cc vi khun nhy
cm( dng theo ng tim)
- iu tr nhim khun ng h hp
- iu tr nhim khun tai ngoi ( nh vo tai)
m. GRAMYCIDIN
Ngun gc:
Gramycidin c chit ra t dung dch nui cy Bacillus brevis. Ch phm l
mt hn hp khng sinh polypeptid c 4 ng phn gramicidin A, B, C, D m
trong thnh phn ch yu (87%) l gramicidin A. Gramicidin c cu to l
mt polypeptid t 15 aminoaxit ng vng, phn nhnh lun phin, dng L,D.
D- Val - Val - D - Val - Ala - D - Leu - Ala - Gly - Val - CHO
Trp - D - Leu - Trp - D - Leu - Trp - D - Leu - Trp - NH2-CH2CH2OH
20- 286 ( Valin- Gramicindin A )
Thnh phn ch phm dc dng: Gramicidin A (87,5%); B (7,1%); C (5,1%);
D (0,3%); l bt kt tinh mu trng ng, khng mi, khng tan trong nc, ete
cacbua hidro. Tan trong etanol, piridin, axit axetic, to dung dch keo vi nc.
Cng dng : Do khng tan trong nc, b dch c th lm mt hot tnh, c
tnh cao, nn khng dng iu tr nhim khun ton thn. Thng kt hp vi cc
khng sinh nhy cm vi vi khun Gram (-) nh polymycin B, neomycin iu tr
nhim khun da v mt. Thuc m tra mt nng gramicidin 0,0025% ( trong
thnh phn phi hp vi polymycin B).
r. KHNG SINH NHM RIFAMYCIN
Ngun gc:

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T mi trng nui cy Streptomyces mediteranei phn lp c mt s hp

cht khng sinh c hiu lc khng khun thp l rifamycin B, O, S, X. (20-287,
20-288, 20-290 )
Cng thc chung:
T cc khng sinh t nhin (20-287) - (20-290) ngi ta bn tng hp ra cc
khng sinh khc c hot lc mnh hn v c dng trong thc t iu tr l :
rifamycin SV (20-201); rifamide (20-292); rifampin (20-293); rifapentin (20-294);
rifabutin (20-295); rifaximin (20-296).
R
R
R
Rifamycin B (20-287, -OH
-OCH2COOH
-H
1960
Rifamycin O (20-288), =O
-(1,3-dioxolan-4-on)-2-yl -H
1967
Rifamycin S (20-289), =O
=O
-H
1960
Rifamycin X (20-290), =O
=N(+)N(-)
-H
1961
Rifamycin SV (20-291), -OH
OH
-H
1960
Rifamide (20-292),
-OH
OCH2CON(C2H5)2
-H
1963
Rifamipin (20-293),
-OH
OH
cng thc
1966
Rifapentine (20-294),
-OH
OH
cng thc
1976
Rifabutin (20-295),
=O
cng thc
cng thc
1979
Rifaximin (20-296),
-OH
cng thc
cng thc
1981
Cc hp cht trong nhm c ph tc dng cng nh c ch tc dng gn ging nh
nhau.
Trong s cc khng sinh trong nhm ny th rifamycin hay cn gi l rifampin
(20-293) l c s dng nhiu nht.
p. RIFAMPICIN.
Rifampicin l khng sinh bn tng hp s dng nhiu nht, ph bin nht ca
nhm, s dng trong iu tr bnh lao, bnh phong.
Rifampicin. (20-293) c tn gi rifampin, rifadin l rifamycin SV (20-291) gn
nhm th (4-metyl-1-piperazinyl ) imino metyl vo v tr C-3 thay H. S thay i ny
lm cho rifampicin c nhiu u im so vi rifamycin SV: hp thu tt ng tiu
ha, chu c axit d dy nn c th dng c bng ng ung, thi gian tc dng
ko di hn. V vy rifampicin l ch phm c dng ph bin nht.
- Tnh cht vt l ha hc: trong dung dch khng bn, lin kt este d thy phn
- C ch tc dng: c ch enzim tng hp RNA ph thuc DNA ca vi khun
- Dc ng hc : hu nh 100% hp thu theo ng tiu ha
- Ph tc dng
Rifampicin l mt khng sinh ph rng, invitro c tc dng tt vi cu khun
Gram (+) v Gram (-) nhng hiu qu lm sng cha c khng nh.
Rifampicin. Nhy cm vi hu ht cc vi khun Gram (+), mnh nht trn
Staph. Pyrogens, Strrep. Pyrogens v Strep. Viridans; tc dng trn mt s vi
khun Gram (-): H.influenza, Neisseria. c bit nhy cm vi Mycobacterium
tuberculosis v Myco. Leprae ( trc khun lao v phong ). Tuy nhin cc vi khun
nhy cm li khng li rifampicin rt nhanh, tr trc khun lao v phong, v l
hin nay rifampicin t c dng iu tr rng ri m ch yu ch s dng trong
phc phi hp iu tr lao v phong: (iu tr lao: INH + rifampicin + Dapson;
iu tr phong: Rifampicin + Dapson).

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Rifampicin cng cn c dng d phng vim mng no, vim phi do

H.influenza. mt s dng nhim khun do Neisseria.
Ch nh
- iu tr lao kt hp vi cc thuc tr lao khc nh INH, dapson. Ethambutol,
streptomycin.
- iu tr bnh phong: kt hp vi Dapson
- Mt s ch nh khc
+ Vim mng no do Heamophilus influenza v Neisseria meningitides
+ iu tr nhim khun nng do cc Staphylococcus k c cc chng khng
methicillin v a khng.
+ Nhim Mycrobacterium khng in hnh ngi b AIDS cng phi phi
hp vi cc thuc khng khun khc cng ging nh iu tr lao.
Chng ch nh
- Mn cm vi rofampicin
- Ri lon chuyn ha perthytin nhng ngi nhy cm do mt c ch lin
quan ti vic gy cm ng enzim Cytochrom P450 gan.
s. NHM KHNG SINH CHNG NM
Cc khng sinh ny khng tc ng trn vi khun ch tc dng ln nm.
* PHN LOI
C loi c ngun gc sinh hc, c loi c ngun gc tng hp ha hc
Ngun gc sinh hc gm c:
- Cu trc thuc nhm polyen: nystatin (20-297), amphotericin (20-298)
- Grisepfulvin (20-299)
* Ngun gc tng hp
- 5-flu-cytosine
- Dn xut imidazol clotrimazole, miconazole, ketoconazole, itraconazol vv...
Trong chng trnh ny ch cp cc thuc c ngun gc sinh hc, cn cc thuc
tng hp s c cp ti trong chng cc thuc khng nm.
q. NYSTATIN (20-297) V AMPHOTERICIN B (20-298)
Nystatin (20-297) l hp cht c chng strreptomycin noursei, S. aureus v mt
s chng Strreptomyces khc sn sinh ra, cn amphotericin (20-298) do chng
Streptomyces nodosus sn xut ra, c hai u c cu trc gn ging nhau ch c khc
nhau v v tr mt s nhm th trong hp cht. C 2 u thuc nhm cu trc polyen
vongd lacton 36 cnh l loi c bit ca macrolit
- S khc nhau gia natamycin, nystatin v amphotericin B v s lin kt i
- Dc l v c ch tc dng l thuc khng nm ph rng
- C ch tc dng g kt vi sterol ca mng t bo nm
- Ch nh d phng v iu tr nm da v nim mc ( ming, ng tiu ha,
m o).

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TI LIU THAM KHO

1. i Duy Ban, Thuc cha bnh cho ngi v ng vt, NXB Khoa hc v
k thut.
2. Phan nh Chu, Ha dc v k thut tng hp 3, NXB Khoa hc v k
thut.
3. Ha dc - dc l, sch o to dc s trung hc, NXB Y hc.
4. Trnh Thanh oan, Nguyn ng Quang, Hong Trng Ym, Ha hu c,
NXB Gio dc, 1992.
5. ng Nh Ti, C s ha hc lp th, NXB Gio dc H Ni, 1998.
6. Nguyn Minh Tho, Tng hp hu c, NXB i hc Quc gia H Ni.

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MC LC
CHNG 1: Vitamin .......................................................................................... 1
i cng ............................................................................................................ 1
1.1. Cc vitamin tan trong cht bo ..................................................................... 3
1.2. Cc vitamin tan trong nc .......................................................................... 20
CHNG 2: Cht khng sinh ............................................................................ 23
i cng ........................................................................................................... 23
2.1. nh ngha khng sinh ................................................................................. 23
2.2. C ch tc dng ........................................................................................... 24
2.3. n v khng sinh ........................................................................................ 24
2.4. Hot tnh khng sinh c hiu ...................................................................... 24
2.5. Ph khng khun ca khng sinh ................................................................. 24
2.6. Hin tng khng thuc v bn cht khng thuc ca vi sinh vt ................. 24
2.7. iu chnh sinh tng hp khng sinh ........................................................... 26
2.8. Phn nhm khng sinh ................................................................................. 27
2.9. ngha kinh t ca khng sinh .................................................................... 28
2.10. Cc thuc khng sinh nhm -lactam ........................................................ 28
2.11. Cc thuc khng sinh khc ......................................................................... 54
Ti liu tham kho .............................................................................................. 97

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