Professional Documents
Culture Documents
British Journal of
Pharmacology
DOI:10.1111/j.1476-5381.2011.01250.x
www.brjpharmacol.org
REVIEW
bph_1250
Correspondence
184..194
Keywords
novel antibiotics; bacterial
infections; antibiotic resistance;
genomics; non-culturable
bacteria; bacteriophages;
non-multiplying bacteria;
multiplying bacteria
----------------------------------------------------------------
Received
29 December 2010
Revised
13 January 2011
Accepted
14 January 2011
The world is running out of antibiotics. Between 1940 and 1962, more than 20 new classes of antibiotics were marketed.
Since then, only two new classes have reached the market. Analogue development kept pace with the emergence of resistant
bacteria until 1020 years ago. Now, not enough analogues are reaching the market to stem the tide of antibiotic resistance,
particularly among gram-negative bacteria. This review examines the existing systemic antibiotic pipeline in the public
domain, and reveals that 27 compounds are in clinical development, of which two are new classes, both of which are in
Phase I clinical trials. In view of the high attrition rate of drugs in early clinical development, particularly new classes and the
current regulatory hurdles, it does not seem likely that new classes will be marketed soon. This paper suggests that, if the
world is to return to a situation in which there are enough antibiotics to cope with the inevitable ongoing emergence of
bacterial resistance, we need to recreate the prolific antibiotic discovery period between 1940 and 1962, which produced 20
classes that served the world well for 60 years. If another 20 classes and their analogues, particularly targeting gram-negatives
could be produced soon, they might last us for the next 60 years. How can this be achieved? Only a huge effort by
governments in the form of finance, legislation and providing industry with real incentives will reverse this. Industry needs to
re-enter the market on a much larger scale, and academia should rebuild its antibiotic discovery infrastructure to support this
effort. The alternative is Medicine without effective antibiotics.
LINKED ARTICLES
This article is part of a themed issue on Respiratory Pharmacology. To view the other articles in this issue visit
http://dx.doi.org/10.1111/bph.2011.163.issue-1
Abbreviations
DNA, deoxyribonucleic acid; HAP, Hospital acquired pneumonia; HIV/AIDS, human immunodeficiency/ acquired
immunodeficiency syndrome; MRSA, methicillin resistant Staphylococcus aureus; RNA, ribonucleic acide; spp, species; TB,
tuberculosis; VAP Ventilator associated pneumonia
Introduction
The future of modern medicine depends upon effective antibiotics (So et al., 2010). The world produced more than 20
novel classes of antibiotics between 1930 and 1962 (Coates
et al., 2002; Powers, 2004). Since then, only two new classes
of antibiotics have been marketed (Butler and Buss, 2006;
Hair and Kean, 2007; Zappia et al., 2007). Numerous analogues of existing classes have reached the market in this time
period. Meanwhile, multi-drug-resistant bacteria (superbugs)
have emerged throughout the world (Levy and Marshall,
2004), and now half the deaths from clinical infection in
Europe are associated with multi-drug-resistant bacteria
184 British Journal of Pharmacology (2011) 163 184194
New Classes
Marketed
[-----20-----]
Needed
Year:
194050607080902000102030405060708090210010
Figure 1
The number of new classes of antibiotics which have reached the
market, and predictions of novel classes of antibiotics which are
needed during the next 100 years.
The issues
Antibiotic discovery is the key to the continuance of modern
medicine (So et al., 2010). Why is the pharmaceutical industry producing fewer new antibiotic classes now, when the
need is increasing? The reason for the lack of new classes is
not clear, but the following will be discussed later in this
paper: there may be a shortage of new metabolic targets
(Becker et al., 2006). Marketing of analogues is more financially feasible than developing new classes (Devasahayam
et al., 2010), and it used to be thought that current antibiotics
would last almost indefinitely (reviewed in Coates et al.,
2002). The numbers of major pharmaceutical companies
which are engaged in antibiotic discovery decreased substan-
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tially over the past two to three decades; now, only five
remain active in the field (Boucher et al., 2009). Governments
did not increase funding for antibiotic discovery, including
education in this field, fast enough to cope with the rise in
antibiotic resistance (House of Lords, 1998). This is a major
concern for many countries. Meanwhile, regulatory requirements increased, which has elevated the costs of developing
drugs, and the profits from competing products led pharmaceutical companies away from the antibiotic field.
New classes
Can we produce new classes of antibiotics many times faster
than we have achieved over the past 50 years? Although only
two new classes of antibiotics were marketed in the past 10
years, this shows it is still possible to discover and market new
classes. It also suggests that the reason for the lack of new
class development between 1962 and 2000 was that pharmaceutical companies were concentrating on analogue development, perhaps because the toxicity risks associated with
analogues is lower than that for new classes. Whether it will
be possible to increase antibiotic class discovery to the level it
was between 1940 and 1960, is another matter. It may be
difficult to do so, based upon the possibility that most of the
easy-to-discover antibiotics have already been marketed.
Also, the workforce in companies and in the university sector
need to be re-skilled in microbiology and pharmacology, with
particular emphasis on antibiotic discovery, and this will take
decades to achieve and will be very expensive. Most government funding concentrates on the pathogenesis of infectious
disease, and while this is important, if new antibiotics are to
emerge from the university sector, a higher proportion of the
funding must be allocated to antibiotic discovery and development. Thus, to generate the number of new antibiotics
which are needed over the next 100 years, substantially
increased funding from industry and from government will
be required, and should be focused upon antibiotic discovery,
with less funding for microbial pathogenesis.
The emergence of antibiotic resistance is at the heart of
the gradual demise of the antibiotic era. Can we produce
antibiotics which induce resistance at a lower rate than existing antibiotics? This is a key question and will be addressed
further in the section on antibiotic resistance below.
The aims of this review are to discuss the advantages and
disadvantages of continuing antibiotic discovery in the traditional way, namely, more of the same, meaning analogue
development using the Fleming method. The role of the
relentless emergence of antibiotic resistance to all antibiotics
will also be discussed, as well as possible ways to design
British Journal of Pharmacology (2011) 163 184194 185
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Table 1
Main classes of marketed and withdrawn antibiotics
Class examples
b-Lactams
Penicillins
Penicillin G, penicillin V, methicillin, oxacillin, cloxacillin, dicloxacillin, nafcillin, ampicillin, amoxicillin, carbenicillin, ticarcillin,
mezlocillin, piperacillin, azlocillin, temocillin
Cephalosporins
First generation Cephalothin, cephapirin, cephradine, cephaloridine, cefazolin
Second generation Cefamandole, cefuroxime, cephalexin, cefprozil, cefaclor, loracarbef, cefoxitin, cefmetazole
Third generation Cefotaxime, ceftizoxime, ceftriaxone, cefoperazone, ceftazidime, cefixime, cefpodoxime, ceftibuten, cefdinir
Fourth generation Cefpirome, cefepime
Fifth generation1 Ceftaroline2, ceftobiprole3
Carbapenems
Imipenem, meropenem, doripenem
Monobactams
Aztreonam
b-Lactamase inhibitors
Clavulanate, sulbactam, tazobactam
Aminoglycosides
Streptomycin, neomycin, kanamycin, paromomycin, gentamicin, tobramycin, amikacin, netilmicin, spectinomycin, sisomicin, dibekacin,
isepamicin
Tetracyclines
Tetracycline, chlortetracycline, demeclocycline, minocycline, oxytetracycline, methacycline, doxycycline, tigecycline
Rifamycins
Rifampicin (also called rifampin), rifapentine, rifabutin, bezoxazinorifamycin, rifaximin
Macrolides
Erythromycin, azithromycin, clarithromycin
Ketolides
Telithromycin
Lincosamides
Lincomycin, clindamycin
Glycopeptides
Vancomycin, teicoplanin, telavancin
Lipopeptides
Daptomycin
Streptogramins
Quinupristin, dalfopristin, pristinamycin
Sulphonamides
Sulphanilamide, para-aminobenzoic acid, sulfadiazine, sulfisoxazole, sulfamethoxazole, sulfathalidine
Oxazolidinones
Linezolid
Quinolones
Nalidixic acid, oxolinic acid, norfloxacin, pefloxacin, enoxacin, ofloxacin/levofloxacin, ciprofloxacin, temafloxacin, lomefloxacin,
fleroxacin, grepafloxacin, sparfloxacin, trovafloxacin, clinafloxacin, gatifloxacin, moxifloxacin, sitafloxacin
Others
Metronidazole, polymyxin B, colistin, trimethoprim
1
Spectrum combines third generation gram-negatives with methicillin resistant Staphylococcus aureus (MRSA) and multidrug-resistant
Streptococcus pneumoniae.
2
Pending Federal Drugs Administration review.
3
Marketed in Canada and Switzerland; now withdrawn.
186 British Journal of Pharmacology (2011) 163 184194
antibiotics which lead to a lower rate of emergence of resistance. The merits of trying to discover new classes of antibiotics will be discussed, including ways in which this could be
achieved. Finally, the future direction of antibiotic discovery
will be covered, with advantages and disadvantages of different routes.
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Another potential new class, PDF inhibitors, has been abandoned by a number of companies over the past decade
because of resistance emergence.
For gram-negatives, the non-b-lactamase b-lactamaseinhibitor from Novexel has broad coverage against class A, C
and some class D, such as OXA-48, but not those of Acinetobacter; it has no activity against metallo-b-lactamases. Merck
& Co. also have a similar analogue, but there is less information available in public domain about this molecule.
The siderophore monobactams from Basilea and Pfizer
have similar structures but seem to have different activities,
especially against Acinetobacter spp. The combination of
BAL30072 with meropenem seems to cope with many of the
b-lactam-resistance mechanisms in gram-negatives: this is an
example of more than just inhibiting resistance mechanisms,
but of broadening the spectrum. However, none of the developments is a panacea. Even the new class from Anacor/
GlaxoSmithKline has gaps, especially Acinetobacter spp. The
neoglycoside from Achaogen is immune to nearly, but not all,
the aminoglycoside modifying enzymes found in Enterobacteriaceae but is not active against Pseudomonas aeruginosa.
It should be noted that in Table 2, the indications for
products at preclinical, Phase I and Phase II are largely
guesswork
Product
Dalbavancin
Telavancin
Oritavancin
Ceftaroline
TD-1792
Cethromycin
EDP-420
Solithromycin
BC-3781
GSK1322322
Torezolid
Radezolid
PNU-100480
AFN-1252
MUT056399
PTK0796
Delafloxacin
Finafloxacin
Class
Glycopeptide
Glycopeptide
Glycopeptide
Cephalosporin
Glycopeptidecephalosporin hybrid
Ketolide
Ketolide
Fluoroketolide
Pleuromutilin
Peptide deformylase
inhibitor (new class)
Oxazolidinone
Oxazolidinone
Oxazolidinone
FabI Inhibitor
(new class)
FabI Inhibitor
(new class)
Aminomethylcycline
(tetracycline)
Fluoroquinolone
Fluoroquinolone
Table 2
Broad-spectrum including
fluoroquinolone-resistant MRSA
Staphylococci
Staphylococci
TB
Gram-positive
Spectrum
IV/oral
IV/oral
IV
Oral
Oral
IV/oral
IV/oral
Oral
Oral IV
IV/oral
Oral
Oral and IV
IV
IV
IV
IV; once-weekly
Iv/oral
cSSTI,
cSSTI, CAP
Staph infections
Staph infections
TB
SSTI
cSSTI
Community-acquired RTIs
and SSTIs
Community-acquired RTIs
and SSTIs
Community-acquired RTIs
biothreat pathogens
Community-acquired RTIs
Community-acquired RTIs
biothreat pathogens
SSTI, HAP
SSTI, CAP
cSSTI
cSSTI
Indications
Phase III
Phase III
Phase I
Phase I
Phase I
Phase IIa
Phase IIa
Phase I
Phase II
Preclinical
Phase I/II
Phase II/III
Phase III
Phase IIa
Pre-registration
Phase III
Phase III
Phase
Merlion
Rib-X
Novartis (Paratek)
FAB Pharma
Affinium
Pfizer
Rib-X
Trius (DongA)
GlaxoSmithKline
Nabriva
Cempra (Optimer)
Enanta (Shionogi)
Theravance
Forest (Cerexa)
The Medicines
Company (Lilly)
Astellas (Theravance)
Durata Therapeutics
(Pfizer)
Company (Licensor)
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ARM Coates et al.
Spectrum
IV
IV
IV
IV
IV
IV
IV
IV
IV
IV
IV/oral
IV/oral
Iv/oral
cUTI, Hospital-acquired
cIAI, VAP
cUTI, Hospital-acquired
cIAI, VAP
cUTI, cIAI
VAP
cUTI
cUTI, cIAI
cSSTI, cIAI
Indications
MC-1
Ceftazidime/ NXL104
Cephalosporin/blactamase-inhibitor
Monocarbam (siderophore
monobactam)
Ceftaroline/ NXL104
Cephalosporin/blactamase-inhibitor
BAL30072/ meropenem
NXL104
Monobactam/ carbapenem
CXA-101 /tazobactam
(CXA-201)
Penicillin/b-lactamaseinhibitor
BAL30072
CXA-101
Penicillin
Sulfactam (siderophore
monobactam)
GSK2251052
leucyl-tRNA synthase
inhibitor (new class)
Imipenem/ MK-7655
ACHN-490
Aminoglycoside
Carbapenem/blactamase-inhibitor
TP-434
Fluorocycline (tetracycline)
MK-7655
JNJ-Q2
Fluoroquinolone
Non-b-lactam
b-lactamase-inhibitor
(new class)
Product
Class
Continued.
Table 2
Preclinical
Preclinical
Preclinical
Phase II ready
Phase II ready
Phase I
Phase II
Phase I
Phase I
Phase I
Phase
Pfizer
Basilea
Basilea
Merck & Co
Merck & Co
AstraZeneca/Forest
AstraZeneca/Forest
AstraZeneca (Novexel)
Cubist
Cubist
Anacor/GSK
Achaogen
Tetraphase
J&J
Company (Licensor)
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Stage
Compounds
Marketed (prediction)*
No (new classes)
Phase I
11(2)
Phase II
8(0)
Phase III
6(0)
Preregistration
2(0)
Year
1(0)---------------------]
2(0)---------------------]
3(0)---------------------]
2(0)
2010--------------------2015--------------------2020--------
Figure 2
The number of systemic compounds and classes in development and
predictions of the number which will reach the market. Based on
estimates of drugs in development which are published in the public
domain. New classes are in brackets. *Assumptions: percent of compounds which reach the market (CMR International 2009) 6.25%
in Phase I, 25% in Phase II, 50% in Phase III and 75% in Preregistration. Phase II includes drugs which are in Phase I/II, II ready,
II and IIa. Phase III includes drugs in II/III, III ready and III. Market
predictions are shown with which indicates a range of years due to
current uncertainty of the length of time which is required to
complete Phase III trials, for example for hospital-acquired
pneumonia/ventilator-associated pneumonia.
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Future direction
If bacteria continue to develop new resistance mechanisms,
and if the pharmaceutical industry produces novel classes of
antibiotics at the existing rate, the future for medicine is
bleak. In our view, it is unlikely that the industry will dramatically increase the rate of production of new classes of
antibiotics. This means that the present global antibiotic
discovery process is probably unsustainable in the long
term.
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Conclusion
The existing antibiotic pipeline and the infrastructure which
underpins it, is not sufficient to cope with the emergence of
resistance worldwide, particularly among gram-negative bacteria. If the antibiotic discovery process continues at the same
rate as at present More of the same, the antibiotic era will
end within a few decades, at least for many gram-negative
infections.
Potential ways forward include the use of combinations of
antibiotics to reduce the rate of emergence of resistance.
Concentrating on the discovery of compounds that target
complex bacterial systems, such as membranes, could also
reduce resistance emergence.
In the long term, many more new classes of antibiotics are
needed. This will require the intervention of governments
worldwide, with increased grants, subsidies, tax incentives
and an increase in the unit price of new classes of antibiotics.
Universities, charities and regulatory bodies will also need to
change in order to encourage antibiotic discovery.
Acknowledgements
AC and YH would like to acknowledge financial support from
the Medical Research Council, European Commission and
the Burton Trust.
Conflicts of interests
AC is founder, director and shareholder of Helperby Therapeutics Group Ltd which makes new antibiotics targeted at
non-multiplying bacteria. AC and YH receive grants from
Helperby Therapeutics.
References
Andersson DI (2006). The biological cost of mutational antibiotic
resistance: any practical conclusions? Curr Opin Microbiol 9:
461465.
Bax RP, Anderson R, Crew J, Fletcher P, Johnson T, Kaplan E et al.
(1998). Antibiotic resistance what can we do? Nat Med 4:
545546.
Bax BD, Chan PF, Eggleston DS, Fosberry A, Gentry DR, Gorrec F
et al. (2010). Type 11A topoisomerase inhibition by a new class of
antibacterial agents. Nature 19: 935940.
Becker D, Selbach M, Rollenhagen C, Ballmaier M, Meyer TF,
Mann M et al. (2006). Robust salmonella metabolism limits
possibilities for new antimicrobials. Nature 16: 303307.
Boucher HW, Talbot GH, Bradley JS, Edwards JE, Gilbert D, Rice LB
et al. (2009). Bad bugs, no drugs: no ESKAPE! An update from the
Infectious Diseases Society of America. Clin Infect Dis 48: 112.
Brogden RN, Carmine A, Heel RC, Morley PA, Speight TM,
Avery GS (1981). Combination clavulanic acid. Drugs 22: 337362.
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