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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Allosteric Regulation
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Animals
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Anti-Bacterial Agents / pharmacology*
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Bacterial Proteins / antagonists & inhibitors
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Bacterial Proteins / chemistry
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Bacterial Proteins / genetics
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Bacterial Proteins / metabolism
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Drug Synergism
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Drug Therapy, Combination
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Female
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Gene Expression
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Humans
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Linezolid / pharmacology
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Meropenem
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Methicillin Resistance / drug effects*
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Methicillin Resistance / genetics
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Methicillin-Resistant Staphylococcus aureus / chemistry
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Methicillin-Resistant Staphylococcus aureus / drug effects*
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Methicillin-Resistant Staphylococcus aureus / genetics
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Methicillin-Resistant Staphylococcus aureus / isolation & purification
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Mice
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Mice, Inbred ICR
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Microbial Sensitivity Tests
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Operon
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Penicillanic Acid / analogs & derivatives
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Penicillanic Acid / pharmacology
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Penicillin-Binding Proteins
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Piperacillin / pharmacology
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Staphylococcal Infections / drug therapy*
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Staphylococcal Infections / microbiology
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Tazobactam
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Thienamycins / pharmacology
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beta-Lactamase Inhibitors / pharmacology*
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beta-Lactamases / chemistry
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beta-Lactamases / genetics
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beta-Lactamases / metabolism
Substances
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Anti-Bacterial Agents
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Bacterial Proteins
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Penicillin-Binding Proteins
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Thienamycins
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beta-Lactamase Inhibitors
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mecA protein, Staphylococcus aureus
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Penicillanic Acid
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beta-Lactamases
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Meropenem
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Linezolid
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Tazobactam
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Piperacillin