Antibiotic Discovery

Professor Anthony CoatesCentre for Infection

St George’s, University of London

ANTIBIOTIC PIPELINE

Phase II Phase III Market

GRAM Positive 6 (1) 4 ? 3-4Broad Spectrum 4 0 ? 1GRAM Negative 3 (1) 2 ?2

A peptide deformylase inhibitor and a leucyl-tRNA synthase inhibitor

Anthony R M Coates and Gerry Halls. Antibiotics in Phase II and III clinical trials in Antibiotic Resistance. Ed Anthony Coates. Submitted to Handbook of Experimental Pharmacology

Morel C M and Mossialos E. BMJ 2010 Volume 340 March 2010

What can we do?

Make new classes of antibiotics

Rebuild the infrastructure of antibiotic discovery

Why make new classes?

NEW CLASSES

VERSUS

ANALOGUES

New classes are needed to seed extensive antibiotic analogue

developmentClass Examplesβ-Lactams

Penicillins: Penicillin G, penicillin V, methicillin, oxacillin, cloxacillin,dicloxacillin, nafcillin, ampicillin, amoxicillin, carbenicillin,ticarcillin, mezlocillin, piperacillin, azlocillin, temocillin

AminoglycosidesStreptomycin, neomycin, kanamycin, paromomycin, gentamicin, tobramycin, amikacin, netilmicin, spectinomycin, sisomicin, dibekacin, isepamicin

Many new classes needed

Marketed Needed

[-----20-----] [-2--] [-------------?20-----------][-----------?20-------------]

19- 20- 2140—50—60—70—80—90—00—10—20—30—40—50—60—70—80—90—00—10

Coates ARM, Halls G, Hu Y (2011) Novel classes of antibiotics or more of the same? Brit J Pharmacol, 163: 184-194.

Discovery of new classes requires a different approach to the discovery

of analoguesNew class: Structure of class unknown

Structure of target unknownGenomics have not been successful so farWhole cell testing early

New analogue: Structure of class knownStructure of target knownGenomics is usefulWhole bacterial cell testing later

Where do we start?

New ClassesMarketed

Whole bacterial cell assayMultiplying (Fleming) 20+Non-multiplying 0Bacteriophages 0

Metagenomics 0Genomic targets 0

Genomic-New TB targetsacg Hu Y , Coates A (2011) Mycobacterium tuberculosis acg gene is

required for growth and virulence in vivo. PLoS ONE in revision

kshA and kshB Hu Y, van der Geize R, Besra GS, Gurcha SS, Liu A, Rohde M, Singh M, Coates A (2010) 3-Ketosteroid 9α-hydroxylase is an essential factor in the pathogenesis of Mycobacterium tuberculosis. Molecular Microbiology, 75(1), 107-121.

tpx Hu Y, Coates A (2009) Acute and persistent Mycobacterium tuberculosisinfections depend on the Thiol Peroxidase TPX. PLoS ONE, 4(4), e5150

cpn60.1 Hu Y, Henderson B, Lund PA, Tormay P, Ahmed MT, Gurcha SS, Besra GS, Coates AR. A Mycobacterium tuberculosis mutant lacking the groEL homologue cpn60.1 is viable but fails to induce an inflammatory response in animal models of infection. Infect Immun. 2008 Apr;76(4):1535-46. Epub 2008

New class development

Whole bacterial cell target

Lessons from the past

Lessons from tuberculosis

TuberculosisA story of persistence

The life cycle of Mycobacterium tuberculosis

TB PERSISTS

In TB patients, the initial fall in number of bacteria in sputum at the beginning of treatment(fast), is followed

by a slow decline in bacterial counts(slow)

Rustomjee R et al. Int J Tuberc Lung Dis. 2008 Feb;12(2):128-38

Tuberculosis persisters

Survive antibiotic therapy and immune systemTraditionalantibiotics

Time

Bac

teria

Num

bers

SLOW Non-multiplying PERSISTERS

17

FAST Multiplying

After rifampicin treatment,M.tuberculosis continues to incorporate [3H]uridineinto RNA

Are antibiotic resistant/ tolerant persistant Mycobacterium tuberculosis

metabolically active?Radioactive Uridine Update persistent Mycobacterium

tuberculosis

10000

20000

30000

40000

50000

60000

70000

80000

CPM

Before Rifampicin

0

100

200

300

400

500

600

CPM

After Rifampicin

Heat-killed

Persisters in the murine Cornell Model

Viable counts of M.tuberculosis in mice treated with isoniazid and pyrazinamide (Cornell model)

-2 0 2 4 6 8 10 12 14

0

2

4

6

8

Lungs

SpleenLogcfu /organ

Weeks after infection

1/8 lung+ ve1/8 spleen +ve

In mouse, non-multiplying M.tuberculosis is slowly killed byantibacterials. After 14 weeks, apopulation of persistentorganisms remains, which ishighly resistant toantibacterials, cannot grow onculture plates or in liquid broth,and cause tuberculosis aftercessation of therapy.

Detection of M. tuberculosis RNA by RT-PCR before and after treatment with

antituberculousagents

Hu Y et a; (2000) J Bact, 182 (22): 6358-

6365

rRNA mRNA16S sigA sigB 16K rpoB

in vitroBefore ++ + + ++ ++After ++ - + ++ +in vivoBefore ++ + ++ ++ +

After ++ - + ++ -

After treatment withantibacterials, M.tuberculosis

mRNA is present although colony forming units are zero

Is it possible to make new antibiotics against

persisters?

Screen compound libraries from the beginning of the discovery process

against dormant bacteria

Coates A, Hu Y, Bax R, Page C (2002) The future challenges facing the development of new antimicrobial drugs. Nature Reviews, 1: 895-910.

2002-2012Antibiotic Discovery Centre

IndustryHelperby TherapeuticsAntibiotic Discovery

Platform

UniversitySt George’s

Helperby Therapeutics

The History of Helperby’s Antibiotic Discovery Program

Helperby has a novel patented screening platform to select compounds which are active against multi-drug resistant bacteria.

These compounds(new class) have been shown to enhance the effect of old antibiotics against resistant bacteria.

Industrial

• £12 million raised• 10 years• 300 small chemical molecules• 49 patent applications • Clinical trials with lead product• Seven programs

Comparison of kill of non-multiplying Staphylococcus aureus(MSSA) HT61 v marketed antibiotics

0

1

2

3

4

5

6

7

8

0 10 20 30 40 50 60

Concentrations (microgram/ml)

Log

CFU

/ml

AugmentinAzithromycinLevofloxacinLinezolidMupirocinHT61

A

HT61 triggers depolarization of bacterial cell membrane and breakage of cell wall

Helperby Therapeutics Businesss Proprietary

The first antibiotic developed against persisters is in clinical trials

Hu Y, Shamaei-Tousi A, Liu Y, Coates A. PLoS One. 2010 Jul 27;5(7):e11818.

No resistance development to HT61 has been observed in S. aureus so far

0.156

5

10

5

0

2

4

6

8

10

12

Mupirocin HT61

µg/m

l

MIC

MIC (10 generations)

0

2

4

6

8

10

0 10 20 30 40 50

MSC

50 (µ

g/m

l)

passages

Development of Enhancer Program

Old antibiotics Helperby’s Enhancer

• Development of resistance

• Relapse of disease• Prolonged treatment

times

• No resistance generation so far

• Low relapse• Fast kill

Helperby’s Enhancer +

Old antibiotic

• Revive many old antibiotics

• Low development risk • New patents for

combinations with old drugs

By attacking the cell membrane Helperby’s new generation enhancers, in combination with known antibiotics, kill resistant bacteria

Enhancer increases the potency of Antibiotic (E = Enhancer; A = old antibiotic)

BACTERIA

012345678

0 2 4 6 8 10Time (hours)

Log

CFU

/ml

E

A

A + E012345678

0 2 4 6 8 10Time (hours)

Log

CFU

/ml

E

A

A + E

Helperby Therapeutics

The Importance of Enhancers

• Rejuvenate old and existing antibiotics • Source of new patents for combinations• Wide spectrum of clinical indications• Relatively low development risk

Third party opinion of the Helperby approach

• Paper in Nature: Hurdle et al 2011# - membrane-active agents form an important new means of eradicating recalcitrant, non-growing bacteria

• National Institute of Health (NIH) – presented Helperby approach at NIH meeting in Washington D.C. in April 2011 and had considerable interest from them

• NIH has indicated its intention to set aside money for grants in this area##

• NDAs signed with two Pharmaceutical Companies interested in possible partnering arrangements with Helperby

Helperby Therapeutics 34

• # Hurdle JG, O'Neill AJ, Chopra I, Lee RE. Nat Rev Microbiol. 2011 Jan;9(1):62-75. Review.• ## NIH has issued a "cleared council concept" on latent/dormant infections, which means that there will likely be a

solicitation released on that topic (in the next few months)

RegulatorsFDA

Clinical endpoint (4000 patients)

EMA(MHRA)Microbiological endpoint(300-600

patients) eg number of Staphylococcus aureus in nose

Microbiological versus Clinical endpoint for market authorisation

MA Cooper and Schlaes –Nature, April 2011

Microbiological Clinical300-600 patients 4,000 patientsColony Forming Units Death/SSI$4.5-9 million $70 million

Rebuild Antibiotic Discovery infrastructure in

universities and industry

St George’s

University

Industry

Market (Pharma)

University

Tech

PDSRF

TechPhD

ANTIBIOTICDISCOVERY

PhD

University

Industry

Tech

PDSRF

TechPhD

ANTIBIOTICDISCOVERY

PhD

University

Industry

Tech

PDSRF

TechPhD

ANTIBIOTICDISCOVERY

PhD

WI

CNRS

DTI

MPI

UGUAM

UCL UL

US

JIISS

LEMI

KI

Antibiotic Discovery UK

ANTIBIOTIC DISCOVERY UK

SA

UL

SGUL

KC

What would be the cost of marketing 20 new classes of antibiotics?

Research Spending Per New Drug

$43.4 million* - $11.79 billion**

Research Spending for 20 New Drugs

$ 1-200 billion***

*Donald W. Light, and Rebecca Warburton 2011. The London School of Economics and Political Science 1745-8552 BioSocieties 1–17

**Sources: InnoThink Center For Research In Biomedical Innovation; Thomson Reuters Fundamentals via FactSet Research Systems

*** Does not take into account rebuilding antibiotic discovery in Universities and Industry, or the increased costs associated with a new class rather than an analogue

European Antibiotic Recovery PlanEC

BANK EARP FUND

LOAN GRANT

SME UNIVERSITIES/BIG PHARMA

Coates A. (2012)PanEuropean Networks. Science and Technology. 04,2

Revolving loan system

Bank

Revolving door

SMEs

Coates A. (2012)PanEuropean Networks. Science and Technology. 04,2

Conclusion

• New classes of antibiotics are needed• Lessons from tuberculosis• Importance of whole cells in the discovery of

new classes• The Antibiotic Discovery Centre at St George’s• Antibiotic Discovery UK• European Antibiotic Recovery Plan

AcknowledgmentsYanmin Hu, St George’s, University of London

Denis Mitchison, St. George’s, University of London

The European Commission and Partners - StopLatent TB, ANTIRESDEV, PredictTB, BACATTACK

MRC

BBSRC

The Burton Trustees for a program grant

Helperby Therapeutics for a program grant