Syntheses and antimicrobial activities of ogipeptin derivatives.

Novel cyclic peptide derivatives based on ogipeptins A, B, C, and D were synthesized. Starting with a mixture of ogipeptins A-D, a practical four-step synthetic procedure was followed to prepare novel derivatives with various kinds of acyl side chains. Among the 45 new synthetic derivatives identified, the antibacterial activities of compounds 8-3 and 8-38 were comparable with those of ogipeptin A. In in vitro nephrotoxicity screening using LLC-PK1 cells, compounds 8-3 and 8-38 showed significantly lower cytotoxicity (LD20 > 480 µM) than colistin (LD20 = 44.2 µM).

Muraminomicins, new lipo-nucleoside antibiotics from Streptosporangium sp. SANK 60501-structure elucidations of muraminomicins and supply of the core component for derivatization.

We screened for bacterial phospho-N-acetylmuramyl-pentapeptide-translocase (MraY: EC 2.7.8.13) inhibitors with the aim of discovering novel antibiotics and observed inhibitory activity in the culture broth of an actinomycete, SANK 60501. The active compounds, muraminomicins A, B, C, D, E1, E2, F, G, H, and I exhibited strong inhibitory activity against MraY with IC50 values of 0.0105, 0.0068, 0.0104, 0.0099, 0.0115, 0.0109, 0.0089, 0.0134, 0.0186, and 0.0094 µg ml-1, respectively. Although muraminomicin F exhibited favorable antibacterial activity against drug-resistant Gram-positive bacteria, this activity was reduced with the addition of serum. To efficiently supply the core component for chemical modification studies, production was carried out in a controlled trial by adding myristic acid to the medium, and a purification method suitable for large-scale production was successfully developed.

Practical one-step glucuronidation via biotransformation.

We herein report a practical one-step glucuronidation method by biotransformation using Streptomyces sp. SANK 60895. This novel direct method of biotransformation has been shown to be more practical and scalable for glucuronidation than previously reported chemical and enzymatic procedures given its simplicity, high ß-selectivity, cost-effectiveness, and reproducibility. We applied the present method to the synthesis of acyl glucuronide and hydroxy-ß-glucuronide of mycophenolic acid and compound 4, respectively. This method was also shown to be applicable to the N-glucuronidation of various compounds.

Vestaines, novel vasoactive compounds, isolated from Streptomyces sp. SANK 63697.

We conducted a screening program for vasoactive compounds and detected a potent activity in the cultured broth of Streptomyces sp. SANK 63697. From the cultured broth, two active compounds, vestaine A1 and B1, were isolated. The structures of these compounds were elucidated by physicochemical data and spectral analyses, and found to be new compounds.

Studies on novel HIF activators, A-503451s.I. Producing organism, fermentation, isolation and structural elucidation.

In the course of our screening for activators of hypoxia-inducible factor (HIF), A-503451 A and virantmycin were isolated from the cultured broth of an actinomycete strain, Streptomyces sp. SANK 60101. From the same culture, the non-active homologs A-503451 B and D were also isolated. A-503451 A and virantmycin activated HIF-dependent reporter gene expression with EC50 values of 8 and 17 ng ml-1, respectively. They are highly potent activators of HIF and thus may be therapeutically useful for erythropoiesis and neural cell protection.

Structure-based gene targeting discovery of sphaerimicin, a bacterial translocase I inhibitor.

Rise and shine: Using a gene-targeting approach aimed at identifying potential L-threonine:uridine-5'-transaldolases that catalyze the formation of (5'S,6'S)-C-glycyluridine, a new bacterial translocase I inhibitor was discovered from an actinomycete following fermentation optimization.

A-90289 A and B, new inhibitors of bacterial translocase I, produced by Streptomyces sp. SANK 60405.

During the course of screening for translocase I inhibitors, the new liposidomycin-related compounds, A-90289 A and B, were isolated from a culture broth of Streptomyces sp. SANK 60405. The structural elucidations were carried out by NMR and high-resolution mass spectral analyses, and they were classified as members of the liponucleoside antibiotics group with a sulfate group at the C-2' position. A-90289 A and B inhibited bacterial translocase I with IC(50) values of 36.5 ng ml(-1) and 33.8 ng ml(-1), respectively.

A-94964, a novel inhibitor of bacterial translocase I, produced by Streptomyces sp. SANK 60404. I. Taxonomy, isolation and biological activity.

Bacterial phospho-N-acetylmuramyl-pentapeptide translocase (translocase I: EC 2.7.8.13) is a key enzyme in peptidoglycan biosynthesis, and a known target of antibiotics. Here we report a novel nucleoside inhibitor against translocase I, A-94964, isolated from the culture broth of the strain Streptomyces sp. SANK 60404. A-94964 inhibited bacterial translocase I with IC50 value of 1.1 microg/ml, and showed antimicrobial activities against Staphylococcus aureus and Enterococcus faecalis with MIC of 100 and 50 microg/ml, respectively. A-94964 did not show cytotoxicity against mammalian cell lines.

A-102395, a new inhibitor of bacterial translocase I, produced by Amycolatopsis sp. SANK 60206.

Bacterial phospho-N-acetylmuramyl-pentapeptide translocase (translocase I: EC 2.7.8.13) is a key enzyme in peptidoglycan biosynthesis, and a known target of antibiotics. Here we report a new nucleoside inhibitor for translocase I, A-102395, isolated from the culture broth of the strain Amycolatopsis sp. SANK 60206. A-102395 is a new derivative of capuramycin that has the benzene with a uniquely substituted chain instead of an aminocaprolactam. A-102395 is a potent inhibitor of bacterial translocase I with IC50 value of 11 nM, but possesses no antimicrobial activity against various strains tested.

Structural elucidation of A-74528, an inhibitor for 2',5'-phosphodiesterase isolated from Streptomyces sp.

A-74528 (1) is a metabolite of Streptomyces sp. discovered in the screening for 2',5'-oligoadenylate phosphodiesterase inhibitors. The planar structure of 1 was mainly elucidated by NMR techniques including natural abundance INADEQUATE, and the relative configuration and the conformation were elucidated by the analyses of NOEs and assessment of dihedral angles predicted by QUANTA/CHARMm computations and coupling constants. It was proved that 1 is a highly fused polyketide with a side-chain branching site that never appeared before from the nature.

A-503083 A, B, E and F, novel inhibitors of bacterial translocase I, produced by Streptomyces sp. SANK 62799.

Novel nucleoside antibiotics were isolated from the cultured broth of the strain classified as Streptomyces sp. SANK 62799. The strain produced four novel capuramycin derivatives designated as A-503083 A, B, E and F. Their structures were elucidated as 2'-O-carbamoyl derivatives of A-500359 A, B (capuramycin), E and F, respectively. A-503083 A, B, E and F inhibited bacterial phospho-N-acetylmuramyl-pentapeptide-translocase (translocase I: EC 2.7.8.13) with IC50 values of 0.024, 0.038, 0.135 and 17.9 microM, respectively.

Studies on novel bacterial translocase I inhibitors, A-500359s. I. Taxonomy, fermentation, isolation, physico-chemical properties and structure elucidation of A-500359 A, C, D and G.

In the course of our screening for bacterial phospho-N-acetylmuramyl-pentapeptide-translocase (translocase I: EC 2.7.8.13) inhibitors, we found inhibitory activity in the cultured broth of the strain identified as Streptomyces griseus SANK 60196. The strain produced capuramycin and four novel capuramycin derivatives designated as A-500359 A, C, D and G. Purification and structural analysis were performed, and the structures of A-500359 A, C, D and G were elucidated as 6'''-methylcapuramycin, 3'-demethyl-6'''-methylcapuramycin, 2''-deoxy-6'''-methylcapuramycin and 3'-demethylcapuramycin, respectively.