Struktur & Metabolisme sel bakteri

reaksi tk. III reaksi tk. II reaksi tk. I

ANTIBAKTERI
(pengantar antibiotik & penghambat sintesis dinding sel bakteri) Dripa Sjabana, dr., M.Kes
dripa@fk.unair.ac.id

PO4 3-

molekul konstituen molekul makro

in am os ks he Asam amino nu kle otid a

peptidoglikan protein

Molekul prekursor & ATP

RNA DNA

glukosa

Mata Ajar Farmakologi Prodi Pendidikan Dokter Universitas Airlangga 2006

NH4 +
Folat Analog pirimidin & purin

SO4 2-

Sintesis protein Sintesis peptidoglikan Sintesis asam nukleat

dripa@fk.unair.ac.id
Modifikasi dari Katzung (2004)

Target Kerja Antibakteri

I. Enzim sintesis dinding sel II. Ribosom bakteri III. Enzim sintesis nukleotida dan replikasi DNA
B. C. D. E.

Antibiotika dengan Target Kerja

Enzim Sintesis Dinding Sel

A. Beta laktam
1. 2. 3. 4. 5. Penicillin Cephalosporin Monobactam Carbapenem Inhibitor beta-laktamase (clavulanic acid, sulbactam, tazobactam) 6. Vancomycin

Teicoplanin Fosfomycin Bacitracin Cycloserine

dripa@fk.unair.ac.id

dripa@fk.unair.ac.id

Cell Envelope of Bacterium

Outer membrane, lipid bilayer, is present in gram (-) but not gram (+). The peptidoglycan is much thicker in gram (+) than in gram (-). Penicilin-binding proteins (PBPs) are membrane proteins that cros-link peptidoglycan. Beta-lactamase, if present, reside in the periplasmic space or the outer surface of the cytoplasmic membran, when they may destroy beta-lactam antibiotics that penetrate the outer membrane.
dripa@fk.unair.ac.id

BIOSYNTHESIS OF CELL WALL PEPTIDOGLYCAN

Bactoprenol (BP) is the lipid membrane carrier M=Nacetylmuramic acid, Glc=glucose, NAcGlc or G= Nacetylglucosamin e 1= fosfomycin, 2= cycloserine, 3=basitracin, 4=vancomycin, 5=beta-lactam antibiotics.
Katzung (2004)

PBP

Katzung (2004)

dripa@fk.unair.ac.id

TRANSPEPTIDASE

to form a crosslink for cell wall rigidity structure

transpeptidase bound to PBP analog D-AlaD-Ala

Modifikasi dari Katzung (2004)

Figure 44.3 Schematic diagram of the biosynthesis of peptidoglycan in a bacterial cell (e.g. Staphylococcus aureus) with the sites of action of various antibiotics. The hydrophilic disaccharide-pentapeptide is transferred across the lipid cell membrane attached to a large lipid (C55 lipid) by a pyrophosphate bridge (-P-P-). On the outside, it is enzymically attached to the 'acceptor' (the growing peptidoglycan layer). The final reaction is a transpeptidation, in which the loose end of the (gly)5 chain is attached to a peptide side-chain of an M in the acceptor and during which the terminal amino acid (alanine) is lost. The lipid is regenerated by loss of a phosphate group (Pi) before functioning again as a carrier. (M, N-acetylmuramic acid; G, N-acetylglucosamine.) dripa@fk.unair.ac.id
Downloaded from: StudentConsult (on 3 May 2005 08:34 AM) 2005 Elsevier

-lactam AB
inhibitor
dripa@fk.unair.ac.id

Autolytic enzimes

bacterial

bacterial lysis
8

CORE STRUCTURE OF BETA-LACTAM ANTIBIOTIC

PENICILLIN
Subsituted 6-aminopenicillanic acid

CEPHALOSPORIN
Subsituted 7-aminocephslosporic acid

Figure 44.2 Schematic diagram of a single layer of peptidoglycan from a bacterial cell (e.g. Staphylococcus aureus) showing the site of action of the β-lactam antibiotics (more detail in Fig. 44.3). In Staphylococcus aureus the peptide cross-links consist of five glycine residues. Gram-positive bacteria have several layers of peptidoglycan. (NAMA, N-acetylmuramic acid; NAG, N-acetylglucosamine.)

A = thiazolidine ring
dripa@fk.unair.ac.id
Downloaded from: StudentConsult (on 3 May 2005 08:34 AM) 2005 Elsevier

Katzung (2004)

dripa@fk.unair.ac.id

10

CORE STRUCTURE OF BETA-LACTAM ANTIBIOTIC

Penicillin
Penicillin G (iv), VK (po) Antistaphylococcus
Cloxacillin, dicloxacillin (po) Nafcillin, oxacillin (iv)

MONOBACTAM
Subsituted 3-amino-4-methylmonobactamic acid

Extended-spectrum
CARBAPENEM
Subsituted 3-hydroxyethylcarbapenemic acid

Amoxicillin, +clav (po) Piperacillin (iv) Ticarcillin (iv)

Katzung (2004)

dripa@fk.unair.ac.id

11

dripa@fk.unair.ac.id

12

Cephalosporin
1st generation:
Cefadroxil, cefazolin, cephalexin, cepharpirin, cephradine Very active againts gram(+) cocci.

(1)

Cephalosporin
3rd generation:

(2)

2nd generation:
Cefaclor, cefamandole, cefonicid, cefuroxime, cefprozil, loracarbef, ceforanide, cephamycins, cefoxitin, cefmetazole, cefotetan Extended gram(-) coverage

Cefoperazone, cefotaxime, ceftazidime, ceftizoxime, ceftriaxone, cefixime, cefpodoxime proxetil, ceftibuten, moxalactam Expanded gram(-) coverage, + bbb.

4th generation:
cefepime More resistant to hydrolysis by chromosomal beta-lactamases (eg. enterobacter) and some extended spectrum betalaktamases

dripa@fk.unair.ac.id

13

dripa@fk.unair.ac.id

14

Monobactam
Aztreonam Spektrum ~ aminoglycoside

Jelaskan hubungan:
Sulphonamide PABA Folate Bakteri vs. manusia ?

dripa@fk.unair.ac.id

15

dripa@fk.unair.ac.id

16

Jelaskan hubungan:
Trimethoprim Tetrahydrofolate Thymidylate Dihydrofolate reductase Bakteri vs. manusia ?

Bacaan lanjut
Katzung BG ed.(2004). Farmakologi Dasar & Klinik, ed.8, buku 3. Jakarta: Salemba Medika, hal.3-33. Rang HP et al. (2003). Pharmacology, ed.5. London: Elsevier, p.620-643.

Diskusi pada situs internet FK Unair di http://www.fk.unair.ac.id/forum Forum Prodi Dokter

dripa@fk.unair.ac.id

17

dripa@fk.unair.ac.id

18