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Nat Chem Biol. 2015 Nov;11(11):855-61. doi: 10.1038/nchembio.1911. Epub 2015 Sep 14.

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

Author information

1
Center for Genome Sciences &Systems Biology, Washington University School of Medicine, St. Louis, Missouri, USA.
2
Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana, USA.
3
Freimann Life Sciences Center, University of Notre Dame, Notre Dame, Indiana, USA.
4
Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana, USA.
5
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.
6
Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, USA.
7
Department of Biomedical Engineering, Washington University, St. Louis, Missouri, USA.

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.

Comment in

PMID:
26368589
PMCID:
PMC4618095
DOI:
10.1038/nchembio.1911
[Indexed for MEDLINE]
Free PMC Article

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