TY - JOUR
T1 - Synergistic, collaterally sensitive β-lactam combinations suppress resistance in MRSA
AU - Gonzales, Patrick R.
AU - Pesesky, Mitchell W.
AU - Bouley, Renee
AU - Ballard, Anna
AU - Biddy, Brent A.
AU - Suckow, Mark A.
AU - Wolter, William R.
AU - Schroeder, Valerie A.
AU - Burnham, Carey Ann D.
AU - Mobashery, Shahriar
AU - Chang, Mayland
AU - Dantas, Gautam
N1 - Publisher Copyright:
© 2015 Nature America, Inc. All rights reserved.
PY - 2015/11/1
Y1 - 2015/11/1
N2 - 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.
AB - 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.
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U2 - 10.1038/nchembio.1911
DO - 10.1038/nchembio.1911
M3 - Article
C2 - 26368589
AN - SCOPUS:84945262284
SN - 1552-4450
VL - 11
SP - 855
EP - 861
JO - Nature Chemical Biology
JF - Nature Chemical Biology
IS - 11
ER -
