Methicillin-resistant Staphylococcus aureus Bacterial Nitric-oxide Synthase Affects Antibiotic Sensitivity and Skin Abscess Development |
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Authors: | Nina M. van Sorge Federico C. Beasley Ivan Gusarov David J. Gonzalez Maren von K?ckritz-Blickwede Sabina Anik Andrew W. Borkowski Pieter C. Dorrestein Evgeny Nudler Victor Nizet |
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Affiliation: | From the Departments of ‡Pediatrics and ;¶Chemistry and Biochemistry and ;the ‖Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, California 92093 and ;the §Department of Biochemistry, New York University School of Medicine, New York, New York 10016 |
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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. |
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Keywords: | Antibiotics Antimicrobial Peptides Neutrophil Nitric Oxide Nitric-oxide Synthase Staphylococcus aureus Virulence Factors |
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