A trans-Translation Inhibitor is Potentiated by Zinc and Kills Mycobacterium tuberculosis and Nontuberculous Mycobacteria

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