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

  • J Antibiot (Tokyo). 2015 Apr;68(4):271-8. doi: 10.1038/ja.2014.133.
Shajila Siricilla  1 ,  Katsuhiko Mitachi  1 ,  Bajoie Wan  2 ,  Scott G Franzblau  2 ,  Michio Kurosu  1
Affiliations
  • 1. Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, USA.
  • 2. Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, USA.
PMID: 25269459 DOI: 10.1038/ja.2014.133
Abstract

Capuramycin (1) and its analogs are strong translocase I (MurX/MraY) inhibitors. In our structure-activity relationship studies of capuramycin analogs against Mycobacterium tuberculosis (Mtb), we observed for the first time that a capuramycin analog, UT-01320 (3) killed nonreplicating (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 IC50 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 tuberculosis drug.