A <i>trans</i>-Translation Inhibitor is Potentiated by Zinc and Kills <i>Mycobacterium tuberculosis</i> and Nontuberculous Mycobacteria

<i>Mycobacterium tuberculosis</i> 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 <i>trans</i>-translation ribosome rescue pathway to kill <i>M. tuberculosis</i>. Our data demonstrate that MBX-4132 is bactericidal against multiple pathogenic mycobacterial species and kills <i>M. tuberculosis</i> 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 <i>trans</i>-translation is inhibited. Taken together, these data suggest that there is a link between disturbing intracellular metal levels and acylaminooxadiazole-mediated inhibition of <i>trans</i>-translation. These findings provide an important proof-of-concept that <i>trans</i>-translation is a promising antitubercular drug target.