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

Shajila Siricilla, Katsuhiko Mitachi, Bajoie Wan, Scott G. Franzblau, Michio Kurosu

Research output: Contribution to journalArticle

25 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)271-278
Number of pages8
JournalJournal of Antibiotics
Volume68
Issue number4
DOIs
StatePublished - Oct 1 2014

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Mycobacterium tuberculosis
DNA-Directed RNA Polymerases
Bacterial RNA
Structure-Activity Relationship
Inhibitory Concentration 50
Tuberculosis
Oxygen
Enzymes
Pharmaceutical Preparations
capuramycin

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Drug Discovery

Cite this

Discovery of a capuramycin analog that kills nonreplicating Mycobacterium tuberculosis and its synergistic effects with translocase i inhibitors. / Siricilla, Shajila; Mitachi, Katsuhiko; Wan, Bajoie; Franzblau, Scott G.; Kurosu, Michio.

In: Journal of Antibiotics, Vol. 68, No. 4, 01.10.2014, p. 271-278.

Research output: Contribution to journalArticle

Siricilla, Shajila ; Mitachi, Katsuhiko ; Wan, Bajoie ; Franzblau, Scott G. ; Kurosu, Michio. / Discovery of a capuramycin analog that kills nonreplicating Mycobacterium tuberculosis and its synergistic effects with translocase i inhibitors. In: Journal of Antibiotics. 2014 ; Vol. 68, No. 4. pp. 271-278.
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