Sun Daniel, Haste Nina M, Sun Josh, Serafim Mateus Sá Magalhães, Salvioni Anna, Olson Joshua, Cole Jason, Okumura Cheryl, Gallo Richard L, Sakoulas George, O'Donoghue Anthony J, Hensler Mary E, Nizet Victor
Division of Host-Microbe Systems and Therapeutics, Department of Pediatrics, University of California San Diego School of Medicine, La Jolla, CA, USA.
Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego School of Medicine, La Jolla, CA, USA.
Infect Microbes Dis. 2025 Mar;7(1):43-53. doi: 10.1097/im9.0000000000000174. Epub 2025 Jan 27.
Infections refractory to standard antibiotic therapy are contributing to adverse treatment outcomes in patients suffering from deep-seated bacterial infections caused by increasingly resistant pathogens. Adjunctive strategies targeting bacterial virulence factors have been considered to supplement the host immune response in fighting the infection. Previous studies suggest that the FDA-approved anti-inflammatory drug diflunisal inhibits (SA) α-toxin expression by its interaction with the response regulator AgrA. We investigated the broader anti-virulence properties of diflunisal against pathogenic strains of SA and established proof-of-concept for its efficacy in blocking SA virulence. Our studies reveal that diflunisal inhibits α-toxin production, sensitizes SA to cationic antibiotics and human antimicrobial peptides, inhibits the production of the golden pigment staphyloxanthin, and reduces biofilm formation. Molecular docking simulations revealed potential interactions between diflunisal and AgrA binding sites. In addition, sequence alignment of the SA AgrA response regulator demonstrated similarities to other response regulators involved in controlling virulence factor expression. Appreciation of the antivirulence properties of diflunisal supports a therapeutic strategy distinct from structurally similar compounds, such as salicylic acid. The repurposing of diflunisal may mitigate disease severity and provide a unique adjunctive tool in the treatment of SA infection.
对于患有由耐药性日益增强的病原体引起的深部细菌感染的患者，标准抗生素治疗难治的感染正导致不良治疗结果。针对细菌毒力因子的辅助策略已被认为可在对抗感染中补充宿主免疫反应。先前的研究表明，美国食品药品监督管理局（FDA）批准的抗炎药双氯芬酸通过与反应调节因子AgrA相互作用来抑制金黄色葡萄球菌（SA）α-毒素的表达。我们研究了双氯芬酸对SA致病菌株更广泛的抗毒力特性，并确立了其在阻断SA毒力方面疗效的概念验证。我们的研究表明，双氯芬酸可抑制α-毒素的产生，使SA对阳离子抗生素和人类抗菌肽敏感，抑制金色色素葡萄球菌黄素的产生，并减少生物膜形成。分子对接模拟揭示了双氯芬酸与AgrA结合位点之间的潜在相互作用。此外，SA AgrA反应调节因子的序列比对显示出与其他参与控制毒力因子表达的反应调节因子相似。认识到双氯芬酸的抗毒力特性支持了一种不同于结构相似化合物（如水杨酸）的治疗策略。双氯芬酸的重新利用可能会减轻疾病严重程度，并为SA感染的治疗提供一种独特的辅助工具。
