Crotteau Ashley N, Nemeth Ansley M, Melander Roberta J, Melander Christian
Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States.
ACS Med Chem Lett. 2025 Jul 1;16(8):1562-1568. doi: 10.1021/acsmedchemlett.5c00201. eCollection 2025 Aug 14.
An increase in antibiotic resistance and the paucity of new treatment options have led to the present-day antibiotic resistance crisis. is categorized by the World Health Organization as a critical priority. Previously, we reported halogenated aryl 2-aminoimidazole (2-AI) adjuvants that potentiate macrolide antibiotics against ; however, this class of adjuvants exhibits cytotoxicity toward HepG2 cells. In this study we generate a library of 2-AI-benzimidazole adjuvants that potentiate clarithromycin (CLR), and exhibit reduced cytotoxicity. Lead compounds lower the CLR minimum inhibitory concentration (MIC) across a panel of clinical isolates, and have therapeutic indices (TI) up to 6-fold higher than the parent 2-AIs.
抗生素耐药性的增加以及新治疗选择的匮乏导致了当今的抗生素耐药性危机。世界卫生组织将其列为关键优先事项。此前,我们报道了卤代芳基2-氨基咪唑(2-AI)佐剂,其可增强大环内酯类抗生素对[具体病原体未提及]的抗菌活性;然而,这类佐剂对HepG2细胞具有细胞毒性。在本研究中,我们构建了一个2-AI-苯并咪唑佐剂文库,该文库增强了克拉霉素(CLR)的抗菌活性,且细胞毒性降低。先导化合物降低了一组临床分离株的CLR最低抑菌浓度(MIC),并且治疗指数(TI)比母体2-AI高6倍。