Chan Liana C, Park Mihyun, Lee Hong K, Chaili Siyang, Xiong Yan Q, Bayer Arnold S, Proctor Richard A, Yeaman Michael R
Division of Molecular Medicine, Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
Division of Infectious Diseases, Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
Antibiotics (Basel). 2023 May 13;12(5):902. doi: 10.3390/antibiotics12050902.
Virulence factor expression is integral to pathogenicity of . We previously demonstrated that aspirin, through its major metabolite, salicylic acid (SAL), modulates virulence phenotypes in vitro and in vivo. We compared salicylate metabolites and a structural analogue for their ability to modulate virulence factor expression and phenotypes: (i) acetylsalicylic acid (ASA, aspirin); (ii) ASA metabolites, salicylic acid (SAL), gentisic acid (GTA) and salicyluric acid (SUA); or (iii) diflunisal (DIF), a SAL structural analogue. None of these compounds altered the growth rate of any strain tested. ASA and its metabolites SAL, GTA and SUA moderately impaired hemolysis and proteolysis phenotypes in multiple strain backgrounds and their respective deletion mutants. Only DIF significantly inhibited these virulence phenotypes in all strains. The kinetic profiles of ASA, SAL or DIF on expression of (alpha hemolysin), (V8 protease) and their regulators (, , (RNAIII)) were assessed in two prototypic strain backgrounds: SH1000 (methicillin-sensitive ; MSSA) and LAC-USA300 (methicillin-resistant ; MRSA). DIF induced expression which is coincident with the significant inhibition of RNAIII expression in both strains and precedes significant reductions in and expression. The inhibited expression of these genes within 2 h resulted in the durable suppression of hemolysis and proteolysis phenotypes. These results indicate that DIF modulates the expression of key virulence factors in via a coordinated impact on their relevant regulons and target effector genes. This strategy may hold opportunities to develop novel antivirulence strategies to address the ongoing challenge of antibiotic-resistant .
毒力因子表达是……致病性所不可或缺的。我们之前证明，阿司匹林通过其主要代谢产物水杨酸（SAL）在体外和体内调节……毒力表型。我们比较了水杨酸盐代谢产物和一种结构类似物调节……毒力因子表达和表型的能力：（i）乙酰水杨酸（ASA，阿司匹林）；（ii）ASA代谢产物，水杨酸（SAL）、龙胆酸（GTA）和水杨尿酸（SUA）；或（iii）双氟尼酸（DIF），一种SAL结构类似物。这些化合物均未改变任何测试菌株的生长速率。ASA及其代谢产物SAL、GTA和SUA在多种……菌株背景及其各自的缺失突变体中适度损害溶血和蛋白水解表型。只有DIF在所有菌株中显著抑制这些毒力表型。在两种原型菌株背景下评估了ASA、SAL或DIF对（α溶血素）、（V8蛋白酶）及其调节因子（……、……、（RNAIII））表达的动力学曲线：SH1000（甲氧西林敏感……；MSSA）和LAC - USA300（耐甲氧西林……；MRSA）。DIF诱导……表达，这与两种菌株中RNAIII表达的显著抑制同时发生，并先于……和……表达的显著降低。这些基因在2小时内表达受到抑制，导致溶血和蛋白水解表型的持久抑制。这些结果表明，DIF通过对其相关调节子和靶效应基因的协同影响来调节……中关键毒力因子的表达。这种策略可能为开发新型抗毒力策略提供机会，以应对耐抗生素……这一持续挑战。
