caa a22 4500 530098881 20181217030327.0 cr unu---uuuuu 181026e20170203xx s 000 0 eng 10.3929/ethz-b-000128561 doi 10.1038/srep41206 doi (ETHRESEARCH)oai:www.research-collection.ethz.ch:20.500.11850/128561 Surface mediated cooperative interactions of drugs enhance mechanical forces for antibiotic action [Elektronische Daten] [Joseph W. Ndieyira, Joe Bailey, Samadhan B. Patil, Manuel Vögtli, Matthew A. Cooper, Chris Abell, Rachel A. McKendry, Gabriel Aeppli] Sci Rep Open access ethresearch 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. Creative Commons Attribution 4.0 International http://creativecommons.org/licenses/by/4.0 ethresearch Biosensors ethresearch Kinetics ethresearch Ndieyira Joseph W. joint author Bailey Joe joint author Patil Samadhan B. joint author Vögtli Manuel joint author Cooper Matthew A. joint author Abell Chris joint author McKendry Rachel A. joint author Aeppli Gabriel joint author Scientific Reports London : Nature Publishing Group 7, p. 41206 2045-2322 http://hdl.handle.net/20.500.11850/128561 text/html WWW-Backlink auf das Repository (Open access) 1 Journal Article ethresearch ETHRESEARCH 856 40 http://hdl.handle.net/20.500.11850/128561 text/html WWW-Backlink auf das Repository (Open access) ETHRESEARCH 700 1- Ndieyira Joseph W. joint author ETHRESEARCH 700 1- Bailey Joe joint author ETHRESEARCH 700 1- Patil Samadhan B. joint author ETHRESEARCH 700 1- Vögtli Manuel joint author ETHRESEARCH 700 1- Cooper Matthew A. joint author ETHRESEARCH 700 1- Abell Chris joint author ETHRESEARCH 700 1- McKendry Rachel A. joint author ETHRESEARCH 700 1- Aeppli Gabriel joint author ETHRESEARCH 773 0- Scientific Reports London : Nature Publishing Group 7, p. 41206 2045-2322 BK010053 XK010053 XK010000 ETHRESEARCH ETHRESEARCH ETHRESEARCH Journal Article Open access