Methicillin-resistant Staphylococcus aureus bacterial nitric-oxide synthase affects antibiotic sensitivity and skin abscess development

J Biol Chem. 2013 Mar 1;288(9):6417-26. doi: 10.1074/jbc.M112.448738. Epub 2013 Jan 15.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Abscess / genetics
  • Abscess / microbiology
  • Abscess / pathology
  • Animals
  • Anti-Bacterial Agents / pharmacology
  • Antimicrobial Cationic Peptides / pharmacology
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism*
  • Daptomycin / pharmacology
  • Humans
  • Methicillin Resistance*
  • Methicillin-Resistant Staphylococcus aureus / enzymology*
  • Methicillin-Resistant Staphylococcus aureus / genetics
  • Methicillin-Resistant Staphylococcus aureus / pathogenicity*
  • Mice
  • Mutation
  • Nitric Oxide / metabolism
  • Nitric Oxide Synthase / genetics
  • Nitric Oxide Synthase / metabolism*
  • Reactive Oxygen Species / metabolism
  • Staphylococcal Skin Infections / enzymology*
  • Staphylococcal Skin Infections / genetics
  • Staphylococcal Skin Infections / microbiology
  • Staphylococcal Skin Infections / pathology
  • Vancomycin / pharmacology

Substances

  • Anti-Bacterial Agents
  • Antimicrobial Cationic Peptides
  • Bacterial Proteins
  • Reactive Oxygen Species
  • CAP18 lipopolysaccharide-binding protein
  • Nitric Oxide
  • Vancomycin
  • Nitric Oxide Synthase
  • Daptomycin