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. Epub 2014 Oct 1.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminoglycosides / administration & dosage
  • Aminoglycosides / chemistry
  • Aminoglycosides / pharmacology*
  • Antitubercular Agents / administration & dosage
  • Antitubercular Agents / chemistry
  • Antitubercular Agents / pharmacology*
  • Bacterial Proteins / antagonists & inhibitors
  • Caprolactam / administration & dosage
  • Caprolactam / analogs & derivatives*
  • Caprolactam / pharmacology
  • DNA-Directed RNA Polymerases / antagonists & inhibitors
  • Drug Synergism
  • Enzyme Inhibitors / administration & dosage
  • Enzyme Inhibitors / pharmacology*
  • Inhibitory Concentration 50
  • Microbial Sensitivity Tests
  • Mycobacterium tuberculosis / drug effects*
  • Oxygen / metabolism
  • Structure-Activity Relationship
  • Transferases (Other Substituted Phosphate Groups)
  • Transferases / antagonists & inhibitors
  • Uridine / administration & dosage
  • Uridine / analogs & derivatives*
  • Uridine / pharmacology

Substances

  • Aminoglycosides
  • Antitubercular Agents
  • Bacterial Proteins
  • Enzyme Inhibitors
  • SQ-641
  • UT-01320
  • capuramycin
  • Caprolactam
  • Transferases
  • DNA-Directed RNA Polymerases
  • Transferases (Other Substituted Phosphate Groups)
  • mraY protein, Bacteria
  • Oxygen
  • Uridine