Repurposing the Nonsteroidal Anti-inflammatory Drug Diflunisal as an Osteoprotective, Antivirulence Therapy for Staphylococcus aureus Osteomyelitis.

Hendrix AS, Spoonmore TJ, Wilde AD, Putnam NE, Hammer ND, Snyder DJ, Guelcher SA, Skaar EP, Cassat JE
Antimicrob Agents Chemother. 2016 60 (9): 5322-30

PMID: 27324764 · PMCID: PMC4997817 · DOI:10.1128/AAC.00834-16

Staphylococcus aureus osteomyelitis is a common and debilitating invasive infection of bone. Treatment of osteomyelitis is confounded by widespread antimicrobial resistance and the propensity of bacteria to trigger pathological changes in bone remodeling that limit antimicrobial penetration to the infectious focus. Adjunctive therapies that limit pathogen-induced bone destruction could therefore limit morbidity and enhance traditional antimicrobial therapies. In this study, we evaluate the efficacy of the U.S. Food and Drug Administration-approved, nonsteroidal anti-inflammatory (NSAID) compound diflunisal in limiting S. aureus cytotoxicity toward skeletal cells and in preventing bone destruction during staphylococcal osteomyelitis. Diflunisal is known to inhibit S. aureus virulence factor production by the accessory gene regulator (agr) locus, and we have previously demonstrated that the Agr system plays a substantial role in pathological bone remodeling during staphylococcal osteomyelitis. Consistent with these observations, we find that diflunisal potently inhibits osteoblast cytotoxicity caused by S. aureus secreted toxins independently of effects on bacterial growth. Compared to commonly used NSAIDs, diflunisal is uniquely potent in the inhibition of skeletal cell death in vitro Moreover, local delivery of diflunisal by means of a drug-eluting, bioresorbable foam significantly limits bone destruction during S. aureus osteomyelitis in vivo Collectively, these data demonstrate that diflunisal potently inhibits skeletal cell death and bone destruction associated with S. aureus infection and may therefore be a useful adjunctive therapy for osteomyelitis.

Copyright © 2016, American Society for Microbiology. All Rights Reserved.

MeSH Terms (21)

Animals Anti-Bacterial Agents Anti-Inflammatory Agents, Non-Steroidal Bacterial Proteins Bone Density Conservation Agents Cell Survival Delayed-Action Preparations Diflunisal Drug Repositioning Female Gene Expression Humans Mice Mice, Inbred C57BL Osteoblasts Osteomyelitis Primary Cell Culture Staphylococcal Infections Staphylococcus aureus Trans-Activators Treatment Outcome

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