Journal
NATURE CHEMICAL BIOLOGY
Volume 11, Issue 11, Pages 855-U71Publisher
NATURE PORTFOLIO
DOI: 10.1038/nchembio.1911
Keywords
-
Categories
Funding
- NIH
- National Institute of Diabetes and Digestive and Kidney Diseases
- National Institute of General Medical Sciences of the National Institutes of Health (NIH) [DP2DK098089, R01GM099538]
- National Institute of Allergy and Infectious Diseases of the NIH [AI90818, AI104987]
- NIGMS Cell and Molecular Biology Training Grant [GM007067]
- NIH [T32 GM075762, F31 AI115851]
Ask authors/readers for more resources
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 beta-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-beta-lactamase inhibitor combinations. ME/PI/TZ circumvents the tight regulation of the mec and bla operons in MRSA, the basis for inducible resistance to beta-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 beta-lactam antibiotics could be effective against MRSA infections in humans.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available