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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