Antibiotics

Current Challenges

Christopher Walsh
Harvard Medical School
Department of Biological Chemistry and Molecular Pharmacology

Pictures of the pathogens

Staphylococcus aureus

Enterococcus faecalis

Klebsiella pneumoniae

Pseudomonas aeruginosa

Mycobacterium tuberculosis

Acinetobacter spp.

http://www.denniskunkel.com (2007)

Gram staining of bacterial cells

Gram-positive

Gram-negative

Cell wall: Gram-positive vs. Gram-negative

Pictures of the pathogens

Staphylococcus aureus

Enterococcus faecalis

Klebsiella pneumoniae

Pseudomonas aeruginosa

Mycobacterium tuberculosis

Acinetobacter spp.

http://www.denniskunkel.com (2007)

Where have we been?

The market for antibiotics

Global market for antibiotics: $23-30 billion

Best-selling antibiotic: Levaquin, $2.4 billion
Fast-growing classes: Glycopeptides, carbapenems,
oxazolidinones

The market for antibiotics

Generic antibiotics in widespread use:

Two lines of antibiotic discovery

1. Finding antimicrobial chemical weaponry in

nature
Natural product discovery

2. Manmade magic bullets

Synthetic chemicals turned into antibiotics

Antibiotics: Natural and synthetic

Natural product antibiotics

-lactams
Erythromycin
Tetracycline
Streptomycin & related aminoglycosides
Vancomycin

Synthetic antibiotics
Sulfamethoxazole/trimethoprim
Quinolones (Cipro)
Oxazolidinones

Antibiotics: Modes of action

Walsh, C.T., Antibiotics (2003) ASM Press

Antibiotics: Modes of action

Walsh, C.T., Antibiotics (2003) ASM Press

Antibiotics: Modes of action

Walsh, C.T., Antibiotics (2003) ASM Press

Antibiotics: Modes of action

Walsh, C.T., Antibiotics (2003) ASM Press

Antibiotics: Modes of action

Walsh, C.T., Antibiotics (2003) ASM Press

The past

The Golden Age of antibiotic discovery was

very brief: 1930s-1950s
Penicillin
Cephalosporin
Streptomycin
Erythromycin
Tetracycline
Vancomycin

Semisynthetic modification of antibacterial

natural products

Is there still opportunity for innovation?

4 generations of cephalosporins
3 generations of erythromycins

ceftazidime

2 generations of carbapenems

ertapenem

3 generations of tetracyclines

tigecycline

telithromycin

Generations of semisynthetic antibiotics

Convergence of natural product biosynthesis and medicinal chemistry

modifications

Generations of semisynthetic antibiotics

Convergence of natural product biosynthesis and medicinal chemistry

modifications

New antibacterial agents approved in the U.S.

von Nussbaum et al., Angew. Chem. Int. Ed. 45, 5072 (2006)

An innovation gap for new antibiotic classes

Where now?

The present

Antibiotics against four major target classes in

bacteria
Multi-resistant bacteria are on the rise
Deeper understanding of pathogens coming
from bacterial genomics

Antibiotic resistance

Use of antibiotic selects for growth of rare resistant

organisms in an otherwise susceptible population
Large numbers of bacteria and short generation times
lead to emergence of resistance
Resistance genes collected on plasmids and
transposable elements lead to rapid spread of
multi-drug resistance
Resistance is inevitable; the kinetics may be in doubt

Clinical resistance can emerge rapidly

Antibiotic

Year
Resistance
Deployed Observed

Sulfonamides
Penicillin
Streptomycin
Chloramphenicol
Tetracycline
Erythromycin
Vancomycin
Methicillin
Ampicillin
Cephalosporins

1930s
1943
1943
1947
1948
1952
1956
1960
1961
1960s

1940s
1946
1959
1959
1953
1988
1988
1961
1973
late 1960s
Palumbi, Science 293, 1786 (2001)

New pathogens: Emergence of MRSA

Estimate: 94,360 cases of invasive MRSA leading to

18,650 deaths in 2005 (~20% mortality)

Genotyping and epidemiology suggest that ~85% of

MRSA infections are due to strains of health care
origin
Klevens et al, JAMA (2007) 298, 1763
Appelbaum, Clin Microbiol Infect (2006) 12 (Suppl 2), 3

Vancomycin-resistant enterococci (VRE)

Percent resistant

VRE in ICUs

Opportunistic pathogen in immunocompromised patients, with

high mortality (25%)
Second-most prevalent gram-positive pathogen in U.S.
hospitals
Ammerlaan & Bonten (2006) Clin Microbiol Infect 12 (Suppl 8), 22
http://www.cdc.gov/ncidod/dhqp/nnis_pubs.html

Daptomycin: A new lipopeptide antibiotic

Daptomycin was approved in 2003 for the treatment of skin and

skin structure infections caused by gram-positive bacteria
Active against MRSA and VRSA; MIC = 0.5 g/ml
As acyl chain length increases, potency and toxicity both
increase; C10 (daptomycin) has the highest therapeutic index
Baltz et al (2005) Nat Prod Rep 22, 717

New antibiotics for multi-resistant

Gram-negatives?

The threat of vancomycin resistance led to the

approval of three new drugs: Synercid, Linezolid,
and Daptomycin
New threat: Multi-resistant Gram-negative pathogens
Current options: -lactams, fluoroquinolones,
sulfa/trimethoprim, aminoglycosides, glycylcyclines
A special need for new drugs to treat Gram-negatives?

Pictures of the pathogens

Staphylococcus aureus

Enterococcus faecalis

Klebsiella pneumoniae

Pseudomonas aeruginosa

Mycobacterium tuberculosis

Acinetobacter spp.

http://www.denniskunkel.com (2007)

New pathogens: Multi-resistant

Gram-negatives

Klebsiella
pneumoniae

Pseudomonas
aeruginosa

Acinetobacter
spp.

Resistance
profile

Fluoroquinolones
Co-trimoxazole
Cephalosporins

3 or more of these:
Penicillins
Cephalosporins
Fluoroquinolones
Carbapenems
Aminoglycosides

Fluoroquinolones
Aminoglycosides
All -lactams

Prevalence

21%
(ICUs in USA, 2003)

14%
(ICUs in USA, 2002)

33-53%
(15 centers in North
America, 2006)

Treatment
options

Carbapenems
Tigecycline

Colistin

Tigecycline
Sulbactam
Colistin

Giske et al, Antimicrob Agents Chemother (2007) doi:10.1128/AAC.01169-07

Falagas et al, BMC Infect Dis (2005) 5, 24

Recently approved antibiotics:

Quinolones

Moxifloxacin approved in 1999

Will the useful lifetimes of subsequent generations
decrease?

Recently approved antibiotics:

Glycylcyclines

Advantages of tigecycline
Active against tetracycline-resistant bacteria
Active against MRSA and most Gram-negatives

Prospects for tigecycline

How long will it take for resistance to arise?
Will other glycylcyclines follow?

The future

Multi-drug resistant pathogens widespread

Newly-emerging bacterial diseases (including
zoonoses?)

Where will new antibiotics come from?

Sources of new molecules?

Continued screening
Marine organisms/cyanobacteria
The unculturable metagenome

Synthetic libraries from combinatorial chemistry

or structural biology
Natural product-like complexity and architecture

Combinatorial biosynthesis
Reprogramming antibiotic assembly lines

Telithromycin: One more H-bond than

erythromycin to 23S rRNA in 50S subunit

erythromycin

telithromycin

Tu, et al. Cell, 2005, 121, 257-270.

New antifolates

Hawser et al, Biochem Pharm (2006) 71, 941

New antifolates

Hawser et al, Biochem Pharm (2006) 71, 941

New antifolates

Hawser et al, Biochem Pharm (2006) 71, 941

New inhibitors of lipid synthesis

Fatty acid biosynthesis is an essential pathway for bacterial

membrane phospholipid production
No fatty acid biosynthesis inhibitors are currently
used as antibiotics outside of TB treatment

Wang et al (2006) Nature 441, 358 (Merck)

Jin et al (2006) JACS 128, 10660
Zhang et al (2006) J Biol Chem 281, 17541

New lipid synthesis inhibitors: Platensimycin

Discovered by screening 83,000

natural product extracts
Blocks fatty acid biosynthesis by
inhibiting the ketosynthase FabF
The screen focused on FabF
inhibitors by using antisense RNA to
knock down FabF protein levels in
S. aureus
MIC: 0.5 g/ml against S. aureus (more potent than linezolid)
Platensimycin shows low toxicity and no cross-resistance to multiresistant gram-positive bacterial strains
Wang et al (2006) Nature 441, 358 (Merck)
Young et al (2006) Antimicrob Agents Chemother 50, 519 (Merck)

Looking forward

Generations of scaffold tailoring

New scaffolds for generations of tailoring?

Combination therapy and/or drug cycling

Combination therapy is routinely used for the treatment of HIV

infections and in cancer chemotherapy

Combination therapy and/or drug cycling

Could new combination therapies open the door to using

compounds with high rates of monotherapy resistance?

Is there a Place for

Narrow Spectrum New
Antibiotics?
e.g for MRSA
or multidrug resistant
Acinetobacter