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)