Discovery of a capuramycin analog that kills non-replicating Mycobacterium tuberculosis and its synergistic effects with translocase I inhibitors

Capuramycin (1) and its analogs are strong translocase I (MurX/MraY) inhibitors. In our SAR studies of capuramycin analogs against M. tuberculosis (Mtb), we observed for the first time that a capuramycin analog, UT-01320 (3) killed non-replicating (dormant) Mtb at low concentrations under low-oxygen conditions, whereas selective MurX inhibitors killed only replicating Mtb under aerobic conditions. Interestingly, 3 did not exhibit MurX enzyme inhibitory activity even at high concentrations, however, 3 inhibited bacterial RNA polymerases with the IC(50) values of 100-150 nM range. A new RNA polymerase inhibitor 3 displayed strong synergistic effects with a MurX inhibitor SQ 641 (2), a promising preclinical TB drug.