We have previously reported a series of thiouracil analogs as bacterial SecA inhibitors. In this study, one potent thiouracil analog, SCA-15, was further evaluated for its inhibitory effects on SecA proteins and against strains of methicillin-resistant Staphylococcus aureus (MRSA) and Bacillus anthracis Sterne. SCA-15 inhibited the ion-channel activities of SecA1 with IC₅₀ of 2.0–2.8 μM and the ATPase activities of SecA2 with IC₅₀ of 13–20 μM, respectively. Drug affinity responsive target stability (DARTS) and protein pull-down experiments further supported SaSecA1 and SaSecA2 as the targets of the inhibitor. SCA-15 showed promising bactericidal effects against MRSA and B. anthracis Sterne. In addition, SCA-15 could at least partially overcome the effects of efflux pumps responsible for multidrug resistance. Moreover, SCA-15 also inhibited the secretion of several important toxins of both S. aureus and B. anthracis. These results indicated that targeting SecA is a promising antimicrobial strategy against MRSA and B. anthracis.

我们之前曾报道过一系列硫尿嘧啶类似物作为细菌 SecA 抑制剂。在这项研究中，进一步评估了一种有效的硫尿嘧啶类似物 SCA-15 对 SecA 蛋白以及对耐甲氧西林金黄色葡萄球菌(MRSA) 和炭疽芽孢杆菌Sterne菌株的抑制作用。SCA-15 分别抑制 SecA1 的离子通道活性，IC ₅₀为 2.0–2.8 μM，抑制 SecA2 的 ATPase 活性，IC ₅₀为 13–20 μM。药物亲和力响应目标稳定性 (DARTS) 和蛋白质下拉实验进一步支持 SaSecA1 和 SaSecA2 作为抑制剂的目标。SCA-15 对 MRSA 和炭疽芽孢杆菌显示出有希望的杀菌作用斯特恩。此外，SCA-15 至少可以部分克服导致多药耐药性的外排泵的影响。此外，SCA-15 还抑制了金黄色葡萄球菌和炭疽芽孢杆菌的几种重要毒素的分泌。这些结果表明，靶向 SecA 是一种很有前景的抗 MRSA 和炭疽芽孢杆菌的抗菌策略。