Caprazamycins, Novel Lipo-nucleoside Antibiotics, from Streptomyces sp.

Igarashi, Masayuki; Takahashi, Yoshiaki; Shitara, Tetsuo; Nakamura, Hikaru; Naganawa, Hiroshi; Miyake, T.; Akamatsu, Yuzuru

doi:10.1038/ja.2005.41

Cited by 138 publications

(76 citation statements)

References 13 publications

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“…The deoxysugar moieties of these two clorobiocin analogues show substituted L-rhamnose structures, as clearly shown by the characteristic coupling of the deoxysugar protons. The NMR data of these compounds are in accordance with those reported for other L-rhamnosides (Igarashi et al, 2005;Ströch, 2003), and in contrast to those of 6-deoxy-D-gulosides (Patroni & Stick, 1987). This proves that in the biosynthesis of the deoxysugar moieties of the aminocoumarin antibiotics, the intermediate dTDP-4-keto-6-deoxyglucose undergoes epimerization at both C-3 and C-5.…”

Section: Discussionsupporting

confidence: 73%

Biosynthesis of the unusual 5,5-gem-dimethyl-deoxysugar noviose: investigation of the C-methyltransferase gene cloU

Freitag

Heide

2006

Microbiology

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The aminocoumarin antibiotic clorobiocin contains an unusual branched deoxysugar with a 5,5-gem-dimethyl structure. Inactivation of the putative C-methyltransferase gene cloU was carried out, which led to the loss of the axial methyl group at C-5 of this deoxysugar moiety. This result establishes the function of cloU, and at the same time it proves that the biosynthesis of the deoxysugar moiety of clorobiocin proceeds via a 3,5-epimerization of the dTDP-4-keto-6-deoxyglucose intermediate. The inactivation was carried out on a cosmid which contained the entire clorobiocin biosynthetic gene cluster. Expression of the modified cluster in a heterologous host led to the formation of desmethyl-clorobiocin and a structural isomer thereof. Both compounds were isolated on a preparative scale, their structures were elucidated by 1 H-NMR and mass spectroscopy and their antibacterial activity was assayed.

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Section: Discussionsupporting

confidence: 73%

Biosynthesis of the unusual 5,5-gem-dimethyl-deoxysugar noviose: investigation of the C-methyltransferase gene cloU

Freitag

Heide

2006

Microbiology

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“…To date, a variety of nucleoside antibiotics have been reported as translocase I inhibitors, 5 such as mureidomycins, 6 pacidamycins, 7 napsamycins, 8 liposidomycins, 9 tunicamycin, 10 capuramycins, 11-17 muraymycins 18 and caprazamycins. 19,20 In contrast, only a few inhibitors have been reported for the steps of UDP-MurNAc-pentapeptide formation. D-cycloserine and O-carbamyl-D-serine are known inhibitors for D-Ala-D-Ala pathways Alr and Ddl, [21][22][23] and recently a few synthetic compounds were reported as MurF inhibitors.…”

Section: Introductionmentioning

confidence: 99%

A novel assay of bacterial peptidoglycan synthesis for natural product screening

et al. 2009

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Although a large number of microbial metabolites have been discovered as inhibitors of bacterial peptidoglycan biosynthesis, only a few inhibitors were reported for the pathway of UDP-MurNAc-pentapeptide formation, partly because of the lack of assays appropriate for natural product screening. Among the pathway enzymes, D-Ala racemase (Alr), D-Ala:D-Ala ligase (Ddl) and UDPMurNAc-tripeptide:D-Ala-D-Ala transferase (MurF) are particularly attractive as antibacterial targets, because these enzymes are essential for growth and utilize low-molecular-weight substrates. Using dansylated UDP-MurNAc-tripeptide and L-Ala as the substrates, we established a cell-free assay to measure the sequential reactions of Alr, Ddl and MurF coupled with translocase I. This assay is sensitive and robust enough to screen mixtures of microbial metabolites, and enables us to distinguish the inhibitors for D-Ala-D-Ala formation, MurF and translocase I. D-cycloserine, the D-Ala-D-Ala pathway inhibitor, was successfully detected by this assay (IC 50 ¼1.7 lg ml À1 ). In a large-scale screening of natural products, we have identified inhibitors for D-Ala-D-Ala synthesis pathway, MurF and translocase I.

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“…These enzymes include the first enzyme involved in the membrane stage of peptidoglycan synthesis, phospho-N-acetylmuramylpentapeptide translocase (translocase I), that catalyzes the transfer of MurNAc-pentapetide from UDP-MurNAcpentapetide to the lipid carrier undecaprenyl phosphate to form lipid I. There are several known translocase I inhibitors [1], such as mureidomycins [2], pacidamycins [3], napsamycins [4], liposidomycins [5], tunicamycin [6], capuramycins [7ϳ13], muraymycins [14] and caprazamycins [15,16]. They exhibit antimicrobial activity against various strains including multidrug-resistant ones, and show bactericidal activity [15,17,18].…”

Section: Introductionmentioning

confidence: 99%

A-94964, a Novel Inhibitor of Bacterial Translocase I, Produced by Streptomyces sp. SANK 60404

et al. 2008

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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 IC 50 value of 1.1 m g/ml, and showed antimicrobial activities against Staphylococcus aureus and Enterococcus faecalis with MIC of 100 and 50 m g/ml, respectively. A-94964 did not show cytotoxicity against mammalian cell lines.

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Caprazamycins, Novel Lipo-nucleoside Antibiotics, from Streptomyces sp.

Cited by 138 publications

References 13 publications

Biosynthesis of the unusual 5,5-gem-dimethyl-deoxysugar noviose: investigation of the C-methyltransferase gene cloU

Biosynthesis of the unusual 5,5-gem-dimethyl-deoxysugar noviose: investigation of the C-methyltransferase gene cloU

A novel assay of bacterial peptidoglycan synthesis for natural product screening

A-94964, a Novel Inhibitor of Bacterial Translocase I, Produced by Streptomyces sp. SANK 60404

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