The emergence of multidrug-resistant bacteria along with a declining pipeline of clinically useful antibiotics has led to the urgent need for the development of more effective antibacterial agents. Inspired by our recent report on the antibacterial activity of etrasimod, an immunomodulating drug candidate, we prepared a series of etrasimod derivatives by varying substituents on the phenyl ring, altering the central tricyclic aromatic ring, and modifying the carboxyl group. From this series of compounds, indole derivative 24f was identified as the most potent antibacterial compound, with the minimum inhibitory concentration (MIC) values between 2.5 and 10 μM against various Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), S. epidermidis and enterococci. Moreover, 24f exhibited rapid bactericidal activity against S. aureus, low toxicity and hemolytic activity, and a synergistic effect with gentamicin against S. aureus, MRSA, and Enterococcus faecalis. Furthermore, it was shown that neither etrasimod nor 24f affects S. aureus cell membranes. Importantly, 24f did not induce resistance in S. aureus, representing a significant improvement compared to etrasimod. Finally, the antibacterial activity of etrasimod and 24f against S. aureus and MRSA was confirmed in vivo in a Caenorhabditis elegans infection model. Taken together, our study highlights the value of etrasimod and its derivatives as potential antibacterial candidates for combating infections caused by Gram-positive bacteria.

多重耐药细菌的出现以及临床可用抗生素的减少导致迫切需要开发更有效的抗菌药物。受我们最近关于免疫调节候选药物艾曲莫德抗菌活性报道的启发，我们通过改变苯环上的取代基、改变中心三环芳环和修饰羧基，制备了一系列艾曲莫德衍生物。在这一系列化合物中，吲哚衍生物24f被认为是最有效的抗菌化合物，对多种革兰氏阳性菌的最低抑菌浓度（MIC）在2.5至10μM之间，包括耐甲氧西林金黄色葡萄球菌（MRSA）、S .表皮球菌和肠球菌。此外，24f对金黄色葡萄球菌具有快速杀菌活性，毒性和溶血活性低，与庆大霉素对金黄色葡萄球菌、MRSA和粪肠球菌具有协同作用。此外，研究表明，etrasimod 和24f都不影响金黄色葡萄球菌细胞膜。重要的是，24f不会诱导金黄色葡萄球菌产生耐药性，这与依曲莫德相比有显着改善。最后，etrasimod 和24f对金黄色葡萄球菌和 MRSA的抗菌活性在秀丽隐杆线虫感染模型中得到体内证实。综上所述，我们的研究强调了依曲莫德及其衍生物作为对抗革兰氏阳性菌引起的感染的潜在抗菌候选药物的价值。