Varshney Akanksha, Jia Ziyi, Howe Michael D, Keiler Kenneth C, Baughn Anthony D
Department of Molecular Biosciences, The University of Texas at Austin, Austin, Texas 78712, United States.
Department of Microbiology and Immunology, University of Minnesota Medical School, Minneapolis, Minnesota 55455, United States.
ACS Infect Dis. 2025 May 9;11(5):1140-1152. doi: 10.1021/acsinfecdis.4c00963. Epub 2025 Apr 9.
poses a serious challenge for human health, and new antibiotics with novel targets are needed. Here we demonstrate that an acylaminooxadiazole, MBX-4132, specifically inhibits the -translation ribosome rescue pathway to kill . Our data demonstrate that MBX-4132 is bactericidal against multiple pathogenic mycobacterial species and kills in macrophages. We also show that acylaminooxadiazole activity is antagonized by iron but is potentiated by zinc. Our transcriptomic data reveal dysregulation of multiple metal homeostasis pathways after exposure to MBX-4132. Furthermore, we see differential expression of genes related to zinc sensing and efflux when -translation is inhibited. Taken together, these data suggest that there is a link between disturbing intracellular metal levels and acylaminooxadiazole-mediated inhibition of -translation. These findings provide an important proof-of-concept that -translation is a promising antitubercular drug target.
对人类健康构成了严峻挑战，因此需要具有新靶点的新型抗生素。在此，我们证明一种酰基氨基恶二唑MBX - 4132能特异性抑制翻译核糖体拯救途径来杀死……我们的数据表明，MBX - 4132对多种致病性分枝杆菌具有杀菌作用，并能在巨噬细胞中杀死……我们还表明，酰基氨基恶二唑的活性受到铁的拮抗，但受到锌的增强。我们的转录组数据显示，暴露于MBX - 4132后，多种金属稳态途径失调。此外，当翻译受到抑制时，我们观察到与锌感应和外排相关基因的差异表达。综上所述，这些数据表明干扰细胞内金属水平与酰基氨基恶二唑介导的翻译抑制之间存在联系。这些发现提供了一个重要的概念验证，即翻译是一个有前景的抗结核药物靶点。
