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.
Bibliographical noteFunding Information:
We thank R. Mitra for discussions about SNP calling and NGS data analysis; M. Wallace for MRSA SCCmec typing; B. Wang for technical advice on genomic preparations and sequencing; C. Munck, M. Sommer and J. Lehár regarding prior discussions of 23 antibiotics chosen for combinatorial screening; J. Marasa for screening optimization; J. Fries for optimization of plate reader assays; K. Forsberg for discussions on mechanisms of reciprocal collateral sensitivity; T. Crofts for antibiotic structures in figures; and members of G.D.’s lab for helpful general discussion of the project and manuscript. We thank T. Roemer of Merck Research Laboratories for the kind gift of the antisense strains. This work was supported in part by the NIH Director’s New Innovator Award, the National Institute of Diabetes and Digestive and Kidney Diseases and the National Institute of General Medical Sciences of the National Institutes of Health (NIH) under award numbers DP2DK098089 and R01GM099538 to G.D. It is also supported in part by the National Institute of Allergy and Infectious Diseases of the NIH under award numbers AI90818 to M.C. and S.M. and AI104987 to S.M. M.W.P. was supported by the NIGMS Cell and Molecular Biology Training Grant (GM007067). R.B. was supported by T32 GM075762 and by an individual Ruth L. Kirschstein National Research Service Award F31 AI115851 from the NIH. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies.
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