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 colistin resistance 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 sediments Institute of marine Science, Burapha University, Chonburi. 2013
Nature uses combinations Is 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 combinations Antibiotic-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 PENICILLIN ARB* *Clavulanic acid, sulbactam, tazobactam, avibactam
No ARBs for Other antibiotic classes Aminoglycosides eg gentamicin Tetracyclines eg oxytetracycline Rifamycins eg rifampicin Macrolides eg erythromycin Lincosamides eg clindamycin Glycopeptides eg vancomycin Streptogramins eg quinupristin Sulphonamides eg sulfamethoxazole Oxazolidinones eg linezolid Quinolones eg ciprofloxacin Metronidazole Polymyxin eg colistin Trimethoprim Lipopeptide eg daptomycin Fosfomycin Isoniazid Pyrazinamide Ethambutol Quinoline eg bedaquiline
REJUVENATE OLD ANTIBIOTICS with 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
Resistant Bacteria Log CFU/ml Old antibiotic(a) plus ARB(B) kills carbapenem resistant NDM-1 Klebsiella pneumoniae 9 8 7 6 5 4 3 2 1 0 AA B A + B AAAaAAAAAAAAA= Old Antibiotic = ARB 0 5 10 15 20 25 = Old Antibiotic + ARB 30 Time (h) 17
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)