Synergistic, collaterally sensitive β-lactam combinations suppress resistance in MRSA

Patrick R. Gonzales, Mitchell W. Pesesky, Renee Bouley, Anna Ballard, Brent A. Biddy, Mark A. Suckow, William R. Wolter, Valerie A. Schroeder, Carey Ann D. Burnham, Shahriar Mobashery, Mayland Chang, Gautam Dantas

Research output: Contribution to journalArticlepeer-review

89 Scopus citations

Abstract

Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most prevalent multidrug-resistant pathogens worldwide, exhibiting increasing resistance to the latest antibiotic therapies. Here we show that the triple β-lactam combination meropenem-piperacillin-tazobactam (ME/PI/TZ) acts synergistically and is bactericidal against MRSA subspecies N315 and 72 other clinical MRSA isolates in vitro and clears MRSA N315 infection in a mouse model. ME/PI/TZ suppresses evolution of resistance in MRSA via reciprocal collateral sensitivity of its constituents. We demonstrate that these activities also extend to other carbapenem-penicillin-β-lactamase inhibitor combinations. ME/PI/TZ circumvents the tight regulation of the mec and bla operons in MRSA, the basis for inducible resistance to β-lactam antibiotics. Furthermore, ME/PI/TZ subverts the function of penicillin-binding protein-2a (PBP2a) via allostery, which we propose as the mechanism for both synergy and collateral sensitivity. Showing in vivo activity similar to that of linezolid, ME/PI/TZ demonstrates that combinations of older β-lactam antibiotics could be effective against MRSA infections in humans.

Original languageEnglish
Pages (from-to)855-861
Number of pages7
JournalNature Chemical Biology
Volume11
Issue number11
DOIs
StatePublished - Nov 1 2015

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