Overview of antibiotic combination issues. - DNDi · Overview of antibiotic combination issues....
Transcript of Overview of antibiotic combination issues. - DNDi · Overview of antibiotic combination issues....
Overview of antibiotic combination issues.
Professor Anthony Coates
St George’s, University of London
Founder, CSO, Helperby Therapeutics Ltd
The most serious problem is Carbapenem resistant Gram-negatives
• Almost untreatable highly resistant bacteria
• Most are sensitive to colistin but colistinresistance is rising(MCR-1)
• These are the bacteria which may bring modern medicine to an end
Percentage of carbapenem-resistant Klebsiella spp by country (2011-2014)
(CDDEP www.resistancemap.org)
Conclusion
It is difficult to make new classes of antibiotics
A POTENTIAL SOLUTION
COMBINATIONS
Why Combinations?Nature uses combinations*
Streptomyces clavuligerus (cephamycin + clavulanate)
Other Streptomyces (one strain 6 antibiotics (predicted))
Micromonospora (one strain 8-12 antibiotics(predicted))
xx
*Fishbach MA. Combination therapies for combating
antimicrobial resistance. Current opinion in microbiology. 2011, 14, 519-523
XX Srivibool Rattanaporn. LS-6-P-6070 Morphological study of antimicrobial actinomycete producing isolates from marine sedimentsInstitute of marine Science, Burapha University, Chonburi. 2013
Nature uses combinationsIs this why bacterial species can survive for thousands of years in spite of antimicrobial resistance?
Vanessa M. D’Costa et al.
Antibiotic resistance
is ancient Nature 477,
457–461 (22 September 2011)
Doctors use combinations
Doctors use combinationsAntibiotic-Antibiotic
1. Widen the spectrum of bacterial species killed (blind therapy eg ITU)
2. Prevent the emergence of resistance(TB, HIV)
3. Synergy (endocarditis)
4. Shorten the duration(dormant TB)
Doctors use combinations
Antibiotic Resistance Breaker(ARB)
1. Kill highly resistant bacteria(reduce MIC)
eg AMX + Clav
2. Reduce toxicity (lower dose)
Bacteria produce beta-lactamases which destroy penicillins
Beta-lactamase
\b
Bacterium
ARBs BLOCK BETA-LACTAMASE
ARB*PENICILLIN
*Clavulanic acid, sulbactam, tazobactam, avibactam
No ARBs forOther antibiotic classes
Aminoglycosides eg gentamicinTetracyclines eg oxytetracyclineRifamycins eg rifampicinMacrolides eg erythromycinLincosamides eg clindamycinGlycopeptides eg vancomycinStreptogramins eg quinupristinSulphonamides eg sulfamethoxazoleOxazolidinones eg linezolidQuinolones eg ciprofloxacin
Metronidazole Polymyxin eg colistinTrimethoprimLipopeptide eg daptomycinFosfomycinIsoniazidPyrazinamideEthambutolQuinoline eg bedaquiline
REJUVENATE OLD ANTIBIOTICSwith
ANTIBIOTIC RESISTANCE BREAKERS
(Combination of old non-penicillin antibiotic with a new small chemical entity or ARB which
boosts the affect of the antibiotic)
Coates, A., Hu, Y., Bax, R. & Page C.( 2002) The future challenges facing the development of new antimicrobial drugs. Nature Rev. Drug Discov. 1, 895-910
Coates A, Hu Y (2014)Antibiotic Resistance Breakers. In Novel Antimicrobial Agents and
Strategies. Eds; Phoenix DA, Harris F, Dennison SR. Wiley-VCH Verlag GmbH & Co. KGaA.
HELPERBY DISCOVERS NON-PENICILLIN ARBs
HT61 enhances the activity of gentamicin in log phase MSSA and MRSA
MSSA MRSA
Hu, Y. and A. R. M. Coates. 2012 The Journal of Antimicrobial Chemotherapy. doi: 10.1093/jac/dks384
Old antibiotic(A) plus ARB(B) kills carbapenem
resistant NDM-1 Klebsiella pneumoniae
17
0
1
2
3
4
5
6
7
8
9
0 5 10 15 20 25 30
Log C
FU
/ml
Time (h)
AA
B
A + B AAAaAAAAAAAAA=
Old Antibiotic
= ARB
= Old Antibiotic + ARB
Resis
tant
Bacte
ria
THE ADVANTAGE OF ARBs
• Re-use antibiotics• Fast development time• Low cost • Potential to boost many classes and all
the analogues within one class
CONCLUSION
• All antibiotics will need to be replaced
due to AMR
• Combinations are an important way forward.
eg Antibiotic Resistance Breakers
Prevent resistance?
Acknowledgements
St George’s, University of London(Yanmin Hu)
Helperby Therapeutics Group plc (15 years).
Antibiotic Discovery-UK(Chris Dowson)Antibiotic Discovery-Global (Jim O’Neil)
Antibiotic Research-UK(Colin Garner)Antibiotic Action (Laura Piddock)
Burton Programme Grant (10 years), European Commission (ANTIRESDEV, BACATTACK, PREDICTB, ENABLE)
MRC, BBSRC, PRF (numerous PhD students)