title: In vitro and ex vivo activity of peptide deformylase inhibitors against Mycobacterium tuberculosis H37Rv.
abstract: Bacterial peptide deformylase (PDF) catalyses removal of the N-terminal formyl group of proteins and is essential for protein maturation, growth and survival of bacteria. Thus, PDF appears to be a good antimycobacterial drug target. In the present study, various well-known PDF inhibitors, such as BB-3497, actinonin, 1,10-phenanthroline, hydroxylamine hydrochloride and galardin, were selected to evaluate their inhibitory activity against Mycobacterium tuberculosis. All compounds were found to be active against M. tuberculosis, with MIC(90) values (lowest drug concentration at which 90% of growth was inhibited on the basis of CFU enumeration) ranging from 0.2 mg/L to 74 mg/L. BB-3497 and 1,10-phenanthroline exhibited potent in vitro antimycobacterial activity, and also showed synergism with isoniazid and rifampicin. All compounds showed a bacteriostatic mode of inhibition. Under ex vivo conditions and short-course chemotherapy, BB-3497 and actinonin were found to be significantly active, with BB-3497 exhibiting comparable efficacy to that of isoniazid. Collectively, promising activities of PDF inhibitors such as BB-3497 and actinonin suggest their potential use against M. tuberculosis.
authors.affiliation: Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556, USA.
authors.forename: Anshika
authors.initials: A
authors.lastname: Sharma
authors.forename: Sadhna
authors.initials: S
authors.lastname: Sharma
authors.forename: G K
authors.initials: GK
authors.lastname: Khuller
authors.forename: A J
authors.initials: AJ
authors.lastname: Kanwar
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D000818:Animals; D000904:Antibiotics, Antitubercular / Q000627:therapeutic use; D004151:Dipeptides / Q000008:administration & dosage; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D006877:Hydroxamic Acids / Q000008:administration & dosage; D019811:Hydroxylamine / Q000008:administration & dosage; D007538:Isoniazid / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology; D010618:Phenanthrolines / Q000008:administration & dosage; D011480:Protease Inhibitors / Q000008:administration & dosage*; D012293:Rifampin / Q000627:therapeutic use; D014376:Tuberculosis / Q000188:drug therapy* / Q000382:microbiology
chemical_list: D000904:Antibiotics, Antitubercular; C425109:BB3497; D004151:Dipeptides; D006877:Hydroxamic Acids; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D010618:Phenanthrolines; D011480:Protease Inhibitors; D019811:Hydroxylamine; D000581:Amidohydrolases; C084507:peptide deformylase; C010531:actinonin; D007538:Isoniazid; D012293:Rifampin; C025205:1,10-phenanthroline