title: Studies on novel bacterial translocase I inhibitors, A-500359s. II. Biological activities of A-500359 A, C, D and G.
abstract: A-500359 A, C, D, G and capuramycin inhibited bacterial phospho-N-acetylmuramyl-pentapeptide-translocase (translocase I: EC 2.7.8.13) with IC50 values of 0.017, 0.12, 0.53, 0.14 and 0.018 microM, respectively. Consistently, A-500359 A, C and capuramycin inhibited in vitro peptidoglycan biosynthesis. A-500359 A exhibited reversible inhibition, which was mixed type and noncompetitive with respect to UDP-MurNAc-(N(epsilon)-Dns)pentapeptide (Ki=0.0079 microM) and undecaprenyl-phosphate, respectively. A-500359 A, C, D and G showed antimicrobial activity against Mycobacterium smegmatis. As a single intravenous injection of A-500359 A at a dose of 500 mg/kg showed no toxicity in mice, it was suggested that the capuramycin derivatives might become candidates as novel therapeutic agents for various diseases caused by Mycobacteria including tuberculosis.
authors.affiliation: Lead Discovery Research Laboratories, Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Muramatsu
authors.forename: Michiko Miyazawa
authors.initials: MM
authors.lastname: Ishii
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Inukai
mesh_terms: D000617:Aminoglycosides; D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D001381:Azepines / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D001419:Bacteria / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D007700:Kinetics; D051379:Mice; D008826:Microbial Sensitivity Tests; D020102:Mycobacterium smegmatis / Q000187:drug effects; D017855:Transferases (Other Substituted Phosphate Groups); D014529:Uridine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity
chemical_list: D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D001381:Azepines; D004791:Enzyme Inhibitors; C049983:capuramycin; D017855:Transferases (Other Substituted Phosphate Groups); C100130:phospho-N-acetylmuramoyl pentapeptide transferase; D014529:Uridine