Boyd Jeffrey M, Price Erin E, Roman Rodriguez Franklin, Burchat Natalie, Norambuena Javiera, DuMont Ashley L, Torres Victor J, Sampath Harini
Department of Biochemistry and Microbiology, Rutgers, The State University of New Jersey, New Brunswick, New Jersey, USA.
Department of Nutritional Sciences, Rutgers, The State University of New Jersey, New Brunswick, New Jersey, USA.
Antimicrob Agents Chemother. 2025 Aug 6;69(8):e0172824. doi: 10.1128/aac.01728-24. Epub 2025 Jun 18.
In the human pathogen , the two-component regulatory system SaeRS contributes to the expression of numerous virulence factors essential for pathogenesis. The kinase and phosphatase activities of SaeS are stimulated by several host and physiological signals, resulting in increased phosphorylation of the transcription factor SaeR and increased transcriptional activity of regulated promoters. It was recently demonstrated that the accumulation of fatty acids negatively impacts SaeS activity, decreasing titers of phosphorylated SaeP and transcriptional output. Triclosan is an effective antimicrobial that has been integrated as an ingredient in a variety of healthcare and consumer products. The chlorinated compound is recalcitrant to natural or biological transformations, resulting in environmental accumulation. At low concentrations, triclosan is a bacteriostatic inhibitor of enoyl-acetyl carrier protein reductase (FabI) of the type II fatty acid synthesis system (FASII), which is necessary for the elongation and synthesis of fatty acids. Herein, we demonstrate that the treatment of with a growth-permissive concentration of triclosan alters the titers of cell-associated fatty acids and thereby functions as an activator of SaeRS. Triclosan-dependent activation of SaeRS subsequently resulted in increased transcription and expression of genes that code for virulence factors. These phenotypes are chemically reversed by the exogenous addition of oleic acid, which inactivates SaeRS, and genetically reversed by crippling the FakAB fatty acid kinase system, which generates phosphorylated fatty acids for incorporation into phospholipids. These findings present implications for the widespread use of triclosan as an antimicrobial agent in household products and its role as a persistent environmental pollutant.
在人类病原体中，双组分调节系统SaeRS有助于许多对发病机制至关重要的毒力因子的表达。SaeS的激酶和磷酸酶活性受到多种宿主和生理信号的刺激，导致转录因子SaeR的磷酸化增加以及受调控启动子的转录活性增强。最近有研究表明，脂肪酸的积累会对SaeS活性产生负面影响，降低磷酸化SaeP的水平和转录输出。三氯生是一种有效的抗菌剂，已被用作各种医疗保健和消费品的成分。这种含氯化合物难以进行自然或生物转化，导致在环境中积累。在低浓度下，三氯生是II型脂肪酸合成系统（FASII）的烯酰-乙酰载体蛋白还原酶（FabI）的抑菌抑制剂，而该酶对于脂肪酸的延长和合成是必需的。在此，我们证明用允许生长浓度的三氯生处理会改变细胞相关脂肪酸的水平，从而起到SaeRS激活剂的作用。三氯生依赖的SaeRS激活随后导致编码毒力因子的基因转录和表达增加。这些表型可通过外源添加油酸（使SaeRS失活）进行化学逆转，也可通过破坏FakAB脂肪酸激酶系统（该系统产生磷酸化脂肪酸以掺入磷脂）进行基因逆转。这些发现对三氯生作为家用抗菌剂的广泛使用及其作为持久性环境污染物的作用具有启示意义。
