Department of Chemistry, Umeå University, SE-90187 Umeå, Sweden.
Department of Molecular Microbiology, Center for Women's Infectious Disease Research, Washington University School of Medicine, St. Louis, 63110 Missouri, United States.
J Med Chem. 2023 Aug 24;66(16):11056-11077. doi: 10.1021/acs.jmedchem.3c00358. Epub 2023 Jul 24.
() drug resistance poses an alarming threat to global tuberculosis control. We previously reported that , a ring-fused thiazolo-2-pyridone, inhibits respiration, blocks biofilm formation, and restores the activity of the antibiotic isoniazid (INH) in INH-resistant isolates. This discovery revealed a new strategy to address INH resistance. Expanding upon this strategy, we identified C10 analogues with improved potency and drug-like properties. By exploring three heterocycle spacers (oxadiazole, 1,2,3-triazole, and isoxazole) on the ring-fused thiazolo-2-pyridone scaffold, we identified two novel isoxazoles, and . and inhibited respiration and biofilm formation more potently with a broader therapeutic window, were better potentiators of INH-mediated inhibition of an INH-resistant mutant, and more effectively inhibited intracellular replication than . The enantiomer showed further enhanced activity compared to its enantiomer and the racemic mixture. Our potent second-generation analogues offer promise for therapeutic development against drug-resistant .
()耐药性对全球结核病控制构成了惊人的威胁。我们之前曾报道过，一种稠合噻唑并[2,3-b]吡啶酮，可抑制呼吸、阻止生物膜形成，并恢复异烟肼（INH）在 INH 耐药结核分枝杆菌中的活性。这一发现为解决 INH 耐药性提供了一种新策略。在此基础上，我们鉴定了具有增强的效力和类药性的 C10 类似物。通过在稠合噻唑并[2,3-b]吡啶酮骨架上探索三种杂环间隔基（噁二唑、1,2,3-三唑和异噁唑），我们鉴定出了两种新型异噁唑，和。和 更有效地抑制了细胞内分枝杆菌的复制，而 对 INH 耐药突变体的 INH 介导的抑制作用具有更强的增效作用，并且具有更宽的治疗窗口，可更有效地抑制呼吸和生物膜形成。与外消旋混合物相比，其对映异构体显示出进一步增强的活性。我们具有潜力的第二代 类似物为开发治疗耐药结核分枝杆菌的药物提供了希望。
