title: The Global Regulon sarA Regulates β-Lactam Antibiotic Resistance in Methicillin-Resistant Staphylococcus aureus In Vitro and in Endovascular Infections.
abstract: BACKGROUND
  The global regulator sarA modulates virulence of methicillin-resistant Staphylococcus aureus (MRSA) via regulation of principal virulence factors (eg, adhesins and toxins) and biofilm formation. Resistance of S. aureus strains to β-lactam antibiotics (eg, oxacillin) depends on the production of penicillin-binding protein 2a (PBP2a), encoded by mecA METHODS:  In the present study, we investigated the impact of sarA on the phenotypic and genotypic characteristics of oxacillin resistance both in vitro and in an experimental endocarditis model, using prototypic healthcare- and community-associated MRSA parental and their respective sarA mutant strain sets.
  
  
  RESULTS
  All sarA mutants (vs respective MRSA parental controls) displayed significant reductions in oxacillin resistance and biofilm formation in vitro and oxacillin persistence in an experimental endocarditis model in vivo. These phenotypes corresponded to reduced mecA expression and PBP2a production and an interdependency of sarA and sigB regulators. Moreover, RNA sequencing analyses showed that sarA mutants exhibited significantly increased levels of primary extracellular proteases and suppressed pyrimidine biosynthetic pathway, argininosuccinate lyase-encoding, and ABC transporter-related genes as compared to the parental strain.
  
  
  CONCLUSIONS
  These results suggested that sarA regulates oxacillin resistance in mecA-positive MRSA. Thus, abrogation of this regulator represents an attractive and novel drug target to potentiate efficacy of existing antibiotic for MRSA therapy.
authors.affiliation: Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center.
authors.forename: Liang
authors.initials: L
authors.lastname: Li
authors.affiliation: Dartmouth Medical School, Hanover, New Hampshire.
authors.forename: Ambrose
authors.initials: A
authors.lastname: Cheung
authors.affiliation: Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center.|Division of Infectious Diseases.|David Geffen School of Medicine at UCLA, Los Angeles, California.
authors.forename: Arnold S
authors.initials: AS
authors.lastname: Bayer
authors.affiliation: Public Health Research Institute, New Jersey Medical School, Rutgers University, Newark.
authors.forename: Liang
authors.initials: L
authors.lastname: Chen
authors.affiliation: Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center.
authors.forename: Wessam
authors.initials: W
authors.lastname: Abdelhady
authors.affiliation: Public Health Research Institute, New Jersey Medical School, Rutgers University, Newark.
authors.forename: Barry N
authors.initials: BN
authors.lastname: Kreiswirth
authors.affiliation: Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center.|Division of Infectious Diseases.|Division of Molecular Medicine, Los Angeles County-Harbor-UCLA Medical Center, Torrance.|David Geffen School of Medicine at UCLA, Los Angeles, California.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Yeaman
authors.affiliation: Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center.|Division of Infectious Diseases.|David Geffen School of Medicine at UCLA, Los Angeles, California.
authors.forename: Yan Q
authors.initials: YQ
authors.lastname: Xiong
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001426:Bacterial Proteins / Q000235:genetics*; D015964:Gene Expression Regulation, Bacterial / Q000235:genetics; D006801:Humans; D008712:Methicillin / Q000494:pharmacology; D016106:Methicillin Resistance / Q000235:genetics*; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects / Q000235:genetics*; D008826:Microbial Sensitivity Tests / Q000379:methods; D010068:Oxacillin / Q000494:pharmacology; D046915:Penicillin-Binding Proteins / Q000235:genetics; D012329:RNA, Bacterial / Q000235:genetics; D018085:Regulon / Q000235:genetics*; D015534:Trans-Activators / Q000235:genetics*; D018440:beta-Lactam Resistance / Q000235:genetics*; D047090:beta-Lactams / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D046915:Penicillin-Binding Proteins; D012329:RNA, Bacterial; C088021:SarA protein, bacterial; D015534:Trans-Activators; D047090:beta-Lactams; D008712:Methicillin; D010068:Oxacillin
keywords: MRSA endocarditis; sarA; treatment; β-lactam antibiotic resistance