title: Methicillin-resistant Staphylococcus aureus bacterial nitric-oxide synthase affects antibiotic sensitivity and skin abscess development.
abstract: Staphylococcus aureus infections present an enormous global health concern complicated by an alarming increase in antibiotic resistance. S. aureus is among the few bacterial species that express nitric-oxide synthase (bNOS) and thus can catalyze NO production from L-arginine. Here we generate an isogenic bNOS-deficient mutant in the epidemic community-acquired methicillin-resistant S. aureus (MRSA) USA300 clone to study its contribution to virulence and antibiotic susceptibility. Loss of bNOS increased MRSA susceptibility to reactive oxygen species and host cathelicidin antimicrobial peptides, which correlated with increased MRSA killing by human neutrophils and within neutrophil extracellular traps. bNOS also promoted resistance to the pharmaceutical antibiotics that act on the cell envelope such as vancomycin and daptomycin. Surprisingly, bNOS-deficient strains gained resistance to aminoglycosides, suggesting that the role of bNOS in antibiotic susceptibility is more complex than previously observed in Bacillus species. Finally, the MRSA bNOS mutant showed reduced virulence with decreased survival and smaller abscess generation in a mouse subcutaneous infection model. Together, these data indicate that bNOS contributes to MRSA innate immune and antibiotic resistance phenotypes. Future development of specific bNOS inhibitors could be an attractive option to simultaneously reduce MRSA pathology and enhance its susceptibility to commonly used antibiotics.
authors: Departments of Pediatrics, University of California, San Diego, California 92093, USA.
authors: Nina M
authors: NM
authors: van Sorge
authors: Federico C
authors: FC
authors: Beasley
authors: Ivan
authors: I
authors: Gusarov
authors: David J
authors: DJ
authors: Gonzalez
authors: Maren
authors: M
authors: von Köckritz-Blickwede
authors: Sabina
authors: S
authors: Anik
authors: Andrew W
authors: AW
authors: Borkowski
authors: Pieter C
authors: PC
authors: Dorrestein
authors: Evgeny
authors: E
authors: Nudler
authors: Victor
authors: V
authors: Nizet
mesh_terms: D000038:Abscess / Q000235:genetics / Q000382:microbiology / Q000473:pathology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D023181:Antimicrobial Cationic Peptides / Q000494:pharmacology; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D017576:Daptomycin / Q000494:pharmacology; D006801:Humans; D016106:Methicillin Resistance; D055624:Methicillin-Resistant Staphylococcus aureus / Q000201:enzymology* / Q000235:genetics / Q000472:pathogenicity*; D051379:Mice; D009154:Mutation; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013207:Staphylococcal Skin Infections / Q000201:enzymology* / Q000235:genetics / Q000382:microbiology / Q000473:pathology; D014640:Vancomycin / Q000494:pharmacology; D054804:Cathelicidins
chemical_list: D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D001426:Bacterial Proteins; D017382:Reactive Oxygen Species; D009569:Nitric Oxide; D014640:Vancomycin; D019001:Nitric Oxide Synthase; D017576:Daptomycin; D054804:Cathelicidins