Repurposing the Nonsteroidal Anti-inflammatory Drug Diflunisal as an Osteoprotective, Antivirulence Therapy for Staphylococcus aureus Osteomyelitis.
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.
Department of Pediatrics, Division of Pediatric Infectious Diseases, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Andrew S
AS
Hendrix
Department of Chemical and Biomedical Engineering, Vanderbilt University, Nashville, Tennessee, USA.
Thomas J
TJ
Spoonmore
Department of Pediatrics, Division of Pediatric Infectious Diseases, Vanderbilt University Medical Center, Nashville, Tennessee, USA Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Aimee D
AD
Wilde
Department of Pediatrics, Division of Pediatric Infectious Diseases, Vanderbilt University Medical Center, Nashville, Tennessee, USA Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Nicole E
NE
Putnam
Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Neal D
ND
Hammer
Department of Pediatrics, Division of Pediatric Infectious Diseases, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Daniel J
DJ
Snyder
Department of Chemical and Biomedical Engineering, Vanderbilt University, Nashville, Tennessee, USA Vanderbilt Center for Bone Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Scott A
SA
Guelcher
Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Eric P
EP
Skaar
Department of Pediatrics, Division of Pediatric Infectious Diseases, Vanderbilt University Medical Center, Nashville, Tennessee, USA Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA Vanderbilt Center for Bone Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA jim.cassat@vanderbilt.edu.
James E
JE
Cassat
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D003692:Delayed-Action Preparations / Q000494:pharmacology*; D004061:Diflunisal / Q000494:pharmacology*; D058492:Drug Repositioning; D005260:Female; D015870:Gene Expression; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects; D010019:Osteomyelitis / Q000188:drug therapy* / Q000382:microbiology / Q000473:pathology; D061251:Primary Cell Culture; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000382:microbiology / Q000473:pathology; D013211:Staphylococcus aureus / Q000187:drug effects / Q000235:genetics / Q000254:growth & development / Q000472:pathogenicity; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016896:Treatment Outcome
C095698:Agr protein, Staphylococcus aureus; D000900:Anti-Bacterial Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001426:Bacterial Proteins; D050071:Bone Density Conservation Agents; D003692:Delayed-Action Preparations; D015534:Trans-Activators; D004061:Diflunisal