Surface mediated cooperative interactions of drugs enhance mechanical forces for antibiotic action.
The alarming increase of pathogenic bacteria that are resistant to multiple antibiotics is now recognized as a major health issue fuelling demand for new drugs. Bacterial resistance is often caused by molecular changes at the bacterial surface, which alter the nature of specific drug-target interactions. Here, we identify a novel mechanism by which drug-target interactions in resistant bacteria can be enhanced. We examined the surface forces generated by four antibiotics; vancomycin, ristomycin, chloroeremomycin and oritavancin against drug-susceptible and drug-resistant targets on a cantilever and demonstrated significant differences in mechanical response when drug-resistant targets are challenged with different antibiotics although no significant differences were observed when using susceptible targets. Remarkably, the binding affinity for oritavancin against drug-resistant targets (70 nM) was found to be 11,000 times stronger than for vancomycin (800 μM), a powerful antibiotic used as the last resort treatment for streptococcal and staphylococcal bacteria including methicillin-resistant Staphylococcus aureus (MRSA). Using an exactly solvable model, which takes into account the solvent and membrane effects, we demonstrate that drug-target interactions are strengthened by pronounced polyvalent interactions catalyzed by the surface itself. These findings further enhance our understanding of antibiotic mode of action and will enable development of more effective therapies.
Departments of Medicine, UCL Institute for Liver and Digestive Health, Royal Free Hospital, London NW3 2QG, UK.|London Centre for Nanotechnology and Departments of Medicine and Physics, University College London, 17-19 Gordon Street, London, WC1H 0AH, United Kingdom.|Department of Chemistry, Jomo Kenyatta University of Agriculture and Technology, Po Box 62000, Nairobi, Kenya.
Joseph W
JW
Ndieyira
London Centre for Nanotechnology and Departments of Medicine and Physics, University College London, 17-19 Gordon Street, London, WC1H 0AH, United Kingdom.|Centre for Mathematics and Physics in the Life Sciences and Experimental Biology, University College London, 17-19 Gordon Street, London, WC1H 0AH, United Kingdom.
Joe
J
Bailey
Departments of Medicine, UCL Institute for Liver and Digestive Health, Royal Free Hospital, London NW3 2QG, UK.
Samadhan B
SB
Patil
Departments of Medicine, UCL Institute for Liver and Digestive Health, Royal Free Hospital, London NW3 2QG, UK.
Manuel
M
Vögtli
Institute for Molecular Bioscience, University of Queensland, Brisbane, 4072, Australia.
Matthew A
MA
Cooper
Department of Chemistry, Lensfield Road, University of Cambridge, Cambridge CB2 1EW, United Kingdom.
Chris
C
Abell
Departments of Medicine, UCL Institute for Liver and Digestive Health, Royal Free Hospital, London NW3 2QG, UK.
Rachel A
RA
McKendry
Laboratory for Solid State Physics, ETH Zurich, Zurich, CH-8093, Switzerland.|Institut de Physique, EPF Lausanne, Lausanne, CH-1015, Switzerland.|Photon Science Division, Paul Scherrer Institut, Villigen PSI, CH-5232, Switzerland.
Gabriel
G
Aeppli
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism*; D001696:Biomechanical Phenomena; D024881:Drug Resistance, Bacterial / Q000187:drug effects*; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects; D006020:Glycopeptides / Q000494:pharmacology; D000077427:Lipoglycopeptides; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D011485:Protein Binding; D012310:Ristocetin / Q000494:pharmacology; D013210:Staphylococcus / Q000187:drug effects* / Q000378:metabolism; D013291:Streptococcus / Q000187:drug effects* / Q000378:metabolism; D013499:Surface Properties; D014640:Vancomycin / Q000031:analogs & derivatives / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D006020:Glycopeptides; D000077427:Lipoglycopeptides; C112142:chloroeremomycin; D012310:Ristocetin; D014640:Vancomycin; C100708:oritavancin