Studies on Novel Bacterial Translocase I Inhibitors, A-500359s. II. Biological Activities of A-500359 A, C, D and G.

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.