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.
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Acknowledgements
The National Institutes of Health is greatly acknowledged for financial support of this work (AI084411). We also thank University of Tennessee for generous financial support. NMR data were obtained on instruments supported by the NIH Shared Instrumentation Grant. The following reagent was obtained through BEI Resources, NIAID, NIH: M. tuberculosis, strain H37Rv and gamma-irradiated M. tuberculosis, NR-14819. The authors gratefully acknowledge Drs William Clemons (California Institute Technology) and Crick (Colorado State University) for useful discussions.
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Siricilla, S., Mitachi, K., Wan, B. et al. Discovery of a capuramycin analog that kills nonreplicating Mycobacterium tuberculosis and its synergistic effects with translocase I inhibitors. J Antibiot 68, 271–278 (2015). https://doi.org/10.1038/ja.2014.133
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DOI: https://doi.org/10.1038/ja.2014.133
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