title: Discovery of a capuramycin analog that kills nonreplicating Mycobacterium tuberculosis and its synergistic effects with translocase I inhibitors.
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.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, USA.
authors.forename: Shajila
authors.initials: S
authors.lastname: Siricilla
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, USA.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Mitachi
authors.affiliation: Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Bajoie
authors.initials: B
authors.lastname: Wan
authors.affiliation: Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Scott G
authors.initials: SG
authors.lastname: Franzblau
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, USA.
authors.forename: Michio
authors.initials: M
authors.lastname: Kurosu
mesh_terms: D000617:Aminoglycosides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D000995:Antitubercular Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors; D002209:Caprolactam / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D012321:DNA-Directed RNA Polymerases / Q000037:antagonists & inhibitors; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D010100:Oxygen / Q000378:metabolism; D013329:Structure-Activity Relationship; D014166:Transferases / Q000037:antagonists & inhibitors; D017855:Transferases (Other Substituted Phosphate Groups); D014529:Uridine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000617:Aminoglycosides; D000995:Antitubercular Agents; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; C000599107:SQ-641; C000599106:UT-01320; C049983:capuramycin; D002209:Caprolactam; D014166:Transferases; D012321:DNA-Directed RNA Polymerases; D017855:Transferases (Other Substituted Phosphate Groups); C079803:mraY protein, Bacteria; D010100:Oxygen; D014529:Uridine