title: Synergistic, collaterally sensitive β-lactam combinations suppress resistance in MRSA.
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.
authors.affiliation: Center for Genome Sciences &Systems Biology, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Patrick R
authors.identifier: http://orcid.org/0000-0003-1594-0233
authors.initials: PR
authors.lastname: Gonzales
authors.affiliation: Center for Genome Sciences &Systems Biology, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Mitchell W
authors.initials: MW
authors.lastname: Pesesky
authors.affiliation: Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana, USA.
authors.forename: Renee
authors.identifier: http://orcid.org/0000-0002-1358-0994
authors.initials: R
authors.lastname: Bouley
authors.affiliation: Center for Genome Sciences &Systems Biology, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Ballard
authors.affiliation: Center for Genome Sciences &Systems Biology, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Brent A
authors.identifier: http://orcid.org/0000-0003-1554-6340
authors.initials: BA
authors.lastname: Biddy
authors.affiliation: Freimann Life Sciences Center, University of Notre Dame, Notre Dame, Indiana, USA.|Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Suckow
authors.affiliation: Freimann Life Sciences Center, University of Notre Dame, Notre Dame, Indiana, USA.|Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana, USA.
authors.forename: William R
authors.initials: WR
authors.lastname: Wolter
authors.affiliation: Freimann Life Sciences Center, University of Notre Dame, Notre Dame, Indiana, USA.|Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana, USA.
authors.forename: Valerie A
authors.initials: VA
authors.lastname: Schroeder
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.|Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Carey-Ann D
authors.initials: CA
authors.lastname: Burnham
authors.affiliation: Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana, USA.
authors.forename: Shahriar
authors.initials: S
authors.lastname: Mobashery
authors.affiliation: Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana, USA.
authors.forename: Mayland
authors.initials: M
authors.lastname: Chang
authors.affiliation: Center for Genome Sciences &Systems Biology, Washington University School of Medicine, St. Louis, Missouri, USA.|Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.|Department of Biomedical Engineering, Washington University, St. Louis, Missouri, USA.
authors.forename: Gautam
authors.initials: G
authors.lastname: Dantas
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D015870:Gene Expression; D006801:Humans; D000069349:Linezolid / Q000494:pharmacology; D000077731:Meropenem; D016106:Methicillin Resistance / Q000187:drug effects* / Q000235:genetics; D055624:Methicillin-Resistant Staphylococcus aureus / Q000737:chemistry / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D051379:Mice; D008813:Mice, Inbred ICR; D008826:Microbial Sensitivity Tests; D009876:Operon; D010397:Penicillanic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D046915:Penicillin-Binding Proteins; D010878:Piperacillin / Q000494:pharmacology; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000382:microbiology; D000078142:Tazobactam; D013845:Thienamycins / Q000494:pharmacology; D065093:beta-Lactamase Inhibitors / Q000494:pharmacology*; D001618:beta-Lactamases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D046915:Penicillin-Binding Proteins; D013845:Thienamycins; D065093:beta-Lactamase Inhibitors; C487789:mecA protein, Staphylococcus aureus; D010397:Penicillanic Acid; D001618:beta-Lactamases; D000077731:Meropenem; D000069349:Linezolid; D000078142:Tazobactam; D010878:Piperacillin