title: Redeploying β-Lactam Antibiotics as a Novel Antivirulence Strategy for the Treatment of Methicillin-Resistant Staphylococcus aureus Infections.
abstract: Innovative approaches to the use of existing antibiotics is an important strategy in efforts to address the escalating antimicrobial resistance crisis. We report a new approach to the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections by demonstrating that oxacillin can be used to significantly attenuate the virulence of MRSA despite the pathogen being resistant to this drug. Using mechanistic in vitro assays and in vivo models of invasive pneumonia and sepsis, we show that oxacillin-treated MRSA strains are significantly attenuated in virulence. This effect is based primarily on the oxacillin-dependent repression of the accessory gene regulator quorum-sensing system and altered cell wall architecture, which in turn lead to increased susceptibility to host killing of MRSA. Our data indicate that β-lactam antibiotics should be included in the treatment regimen as an adjunct antivirulence therapy for patients with MRSA infections. This would represent an important change to current clinical practice for treatment of MRSA infection, with the potential to significantly improve patient outcomes in a safe, cost-effective manner.
authors.affiliation: Department of Clinical Infection, Microbiology and Immunology, Institute of Infection and Global Health, University of Liverpool.
authors.forename: Elaine M
authors.initials: EM
authors.lastname: Waters
authors.affiliation: Department of Microbiology, School of Natural Sciences.
authors.forename: Justine K
authors.initials: JK
authors.lastname: Rudkin
authors.affiliation: School of Mathematics, Statistics, and Applied Mathematics, National University of Ireland, Galway.
authors.forename: Simone
authors.initials: S
authors.lastname: Coughlan
authors.affiliation: Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington.
authors.forename: Geremy C
authors.initials: GC
authors.lastname: Clair
authors.affiliation: Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington.
authors.forename: Joshua N
authors.initials: JN
authors.lastname: Adkins
authors.affiliation: Department of Clinical Infection, Microbiology and Immunology, Institute of Infection and Global Health, University of Liverpool.
authors.forename: Suzanna
authors.initials: S
authors.lastname: Gore
authors.affiliation: Division of Infection, Immunity and Respiratory Medicine, Faculty of Biology, Medicine and Health, University of Manchester, United Kingdom.
authors.forename: Guoqing
authors.initials: G
authors.lastname: Xia
authors.affiliation: Department of Microbiology, School of Natural Sciences.
authors.forename: Nikki S
authors.initials: NS
authors.lastname: Black
authors.affiliation: School of Mathematics, Statistics, and Applied Mathematics, National University of Ireland, Galway.|School of Biotechnology, Dublin City University.
authors.forename: Tim
authors.initials: T
authors.lastname: Downing
authors.affiliation: Department of Clinical Microbiology, Royal College of Surgeons in Ireland, Connolly Hospital, Dublin.
authors.forename: Eoghan
authors.initials: E
authors.lastname: O'Neill
authors.affiliation: Department of Clinical Infection, Microbiology and Immunology, Institute of Infection and Global Health, University of Liverpool.
authors.forename: Aras
authors.initials: A
authors.lastname: Kadioglu
authors.affiliation: Department of Microbiology, School of Natural Sciences.
authors.forename: James P
authors.initials: JP
authors.lastname: O'Gara
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001426:Bacterial Proteins / Q000235:genetics; D004195:Disease Models, Animal; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects; D006801:Humans; D016106:Methicillin Resistance; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects* / Q000235:genetics / Q000472:pathogenicity; D051379:Mice; D008826:Microbial Sensitivity Tests; D010068:Oxacillin / Q000494:pharmacology / Q000627:therapeutic use*; D011023:Pneumonia, Staphylococcal / Q000188:drug therapy / Q000382:microbiology; D053038:Quorum Sensing / Q000235:genetics; D018805:Sepsis / Q000188:drug therapy; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000382:microbiology; D014774:Virulence / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D010068:Oxacillin
keywords: MRSA; antibiotic; attenuation; beta-lactam; virulence