Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Viikinkaari 5 E, FI-00014, Helsinki, Finland.
Drug Research Program, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Viikinkaari 5 E, FI-00014, Helsinki, Finland.
Eur J Med Chem. 2024 Jan 5;263:115921. doi: 10.1016/j.ejmech.2023.115921. Epub 2023 Oct 31.
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.
多种耐药菌的出现以及临床上有用的抗生素数量不断减少，使得开发更有效的抗菌药物成为当务之急。受我们最近关于免疫调节药物候选药物依曲司特的抗菌活性报告的启发，我们通过改变苯环上的取代基、改变中环三环芳环以及修饰羧基，制备了一系列依曲司特衍生物。在这一系列化合物中，吲哚衍生物 24f 被鉴定为最有效的抗菌化合物，对各种革兰氏阳性菌（包括耐甲氧西林金黄色葡萄球菌（MRSA）、表皮葡萄球菌和肠球菌）的最低抑菌浓度（MIC）值在 2.5 至 10 μM 之间。此外，24f 对金黄色葡萄球菌表现出快速杀菌活性，毒性和溶血活性低，并且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，结果表明，依曲司特和 24f 均不影响金黄色葡萄球菌的细胞膜。重要的是，与依曲司特相比，24f 不会诱导金黄色葡萄球菌产生耐药性。最后，在秀丽隐杆线虫感染模型中体内实验证实了依曲司特及其衍生物对金黄色葡萄球菌和 MRSA 的抗菌活性。综上所述，我们的研究强调了依曲司特及其衍生物作为治疗革兰氏阳性菌感染的潜在抗菌候选药物的价值。
