Restoring methicillin-resistant Staphylococcus aureus susceptibility to β-lactam antibiotics

Christopher M. Tan, Alex G. Therien, Jun Lu, Sang H. Lee, Alexandre Caron, Charles J. Gill, Christian Lebeau-Jacob, Liliana Benton-Perdomo, João M. Monteiro, Pedro M. Pereira, Nathaniel L. Elsen, Jin Wu, Kathleen Deschamps, Mihai Petcu, Simon Wong, Etienne Daigneault, Susanne Kramer, Lianzhu Liang, Eugene Maxwell, David ClaveauJohn Vaillancourt, Kathryn Skorey, John Tam, Hao Wang, Timothy C. Meredith, Susan Sillaots, Lisa Wang-Jarantow, Yeeman Ramtohul, Eric Langlois, France Landry, John C. Reid, Gopal Parthasarathy, Sujata Sharma, Anastasia Baryshnikova, Kevin J. Lumb, Mariana G. Pinho, Stephen M. Soisson, Terry Roemer

Research output: Contribution to journalArticle

143 Scopus citations

Abstract

Despite the need for new antibiotics to treat drug-resistant bacteria, current clinical combinations are largely restricted to β-lactam antibiotics paired with β-lactamase inhibitors. We have adapted a Staphylococcus aureus antisense knockdown strategy to genetically identify the cell division Z ring components-FtsA, FtsZ, and FtsW-as β-lactam susceptibility determinants of methicillin-resistant S. aureus (MRSA). We demonstrate that the FtsZ-specific inhibitor PC190723 acts synergistically with β-lactam antibiotics in vitro and in vivo and that this combination is efficacious in a murine model of MRSA infection. Fluorescence microscopy localization studies reveal that synergy between these agents is likely to be elicited by the concomitant delocalization of their cognate drug targets (FtsZ and PBP2) in MRSA treated with PC190723. A 2.0 Å crystal structure of S. aureus FtsZ in complex with PC190723 identifies the compound binding site, which corresponds to the predominant location of mutations conferring resistance to PC190723 (PC190723 R). Although structural studies suggested that these drug resistance mutations may be difficult to combat through chemical modification of PC190723, combining PC190723 with the β-lactam antibiotic imipenem markedly reduced the spontaneous frequency of PC190723 R mutants. Multiple MRSA PC190723 RFtsZ mutants also displayed attenuated virulence and restored susceptibility to β-lactam antibiotics in vitro and in a mouse model of imipenem efficacy. Collectively, these data support a target-based approach to rationally develop synergistic combination agents that mitigate drug resistance and effectively treat MRSA infections.

Original languageEnglish (US)
Article number126ra35
JournalScience Translational Medicine
Volume4
Issue number126
DOIs
StatePublished - Mar 21 2012

All Science Journal Classification (ASJC) codes

  • Medicine(all)

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    Tan, C. M., Therien, A. G., Lu, J., Lee, S. H., Caron, A., Gill, C. J., Lebeau-Jacob, C., Benton-Perdomo, L., Monteiro, J. M., Pereira, P. M., Elsen, N. L., Wu, J., Deschamps, K., Petcu, M., Wong, S., Daigneault, E., Kramer, S., Liang, L., Maxwell, E., ... Roemer, T. (2012). Restoring methicillin-resistant Staphylococcus aureus susceptibility to β-lactam antibiotics. Science Translational Medicine, 4(126), [126ra35]. https://doi.org/10.1126/scitranslmed.3003592