A -Translation Inhibitor is Potentiated by Zinc and Kills and Nontuberculous Mycobacteria.

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.