Synthesis and Antimycobacterial Activity of Capuramycin Analogues. Part 1. Substitution of the Azepan‐2‐one Moiety of Capuramycin.

Hotoda, Hitoshi; al., et

doi:10.1002/chin.200345196

Cited by 10 publications

(12 citation statements)

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“…1). Similar to many other uridyl peptides and uridyl lipopeptides, including liposidomycins (3), tunicamycins (4), capuramycins (5,6), muraymycins (7), and more closely related mureidomycins (8) and napsamycins (9), pacidamycins exhibited antimicrobial activity targeting the translocase MraY to block formation of lipid I from UDP-N-acetylmuramoyl-pentapeptide and undecaprenyl phosphate during bacterial cell wall assembly ( Fig. S1) (10,11).…”

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confidence: 90%

Identification of the biosynthetic gene cluster for the pacidamycin group of peptidyl nucleoside antibiotics

Zhang

Ostash

Walsh³

2010

Proc. Natl. Acad. Sci. U.S.A.

109

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Pacidamycins are a family of uridyl tetra/pentapeptide antibiotics that act on the translocase MraY to block bacterial cell wall assembly. To elucidate the biosynthetic logic of pacidamcyins, a putative gene cluster was identified by 454 shotgun genome sequencing of the producer Streptomyces coeruleorubidus NRRL 18370. The 31-kb gene cluster encodes 22 proteins (PacA-V), including highly dissociated nonribosomal peptide synthetase (NRPS) modules and a variety of tailoring enzymes. Gene deletions confirmed that two NRPSs, PacP and PacO, are required for the biosynthesis of pacidamycins. Heterologous expression and in vitro assays of PacL, PacO, and PacP established reversible formation of m-Tyr-AMP, L-Ala-AMP, and diaminopropionyl-AMP, respectively, consistent with the amino acids found in pacidamycin scaffolds. The unusual Ala 4 -Phe 5 dipeptidyl ureido linkage was formed during in vitro assays containing purified PacL, PacJ, PacN, and PacO. Both the genetic and enzymatic studies validate identification of the biosynthetic genes for this subclass of uridyl peptide antibiotics and provide the basis for future mechanistic study of their biosynthesis.adenylation | ureido-bond | uridine P acidamycins are a family of uridyl tetra/pentapeptide antibiotics isolated from Streptomyces coeruleorubidus. Since their discovery in 1989, at least 10 related compounds have been reported (1, 2), which share a common structural skeleton with a 3′-deoxyuridine nucleoside attached to an N-methyl 2,3-diaminobutyric acid (DABA) residue via a 4′,5′-enamide linkage. Attached to the α-amino of DABA is L-Ala, which is linked to the C-terminal aromatic amino acid via a ureido linkage. An N-terminal amino acid or dipeptide is attached to the β-amino of DABA to give the tetra/pentapeptide framework (Fig. 1). Similar to many other uridyl peptides and uridyl lipopeptides, including liposidomycins (3), tunicamycins (4), capuramycins (5, 6), muraymycins (7), and more closely related mureidomycins (8) and napsamycins (9), pacidamycins exhibited antimicrobial activity targeting the translocase MraY to block formation of lipid I from UDP-N-acetylmuramoyl-pentapeptide and undecaprenyl phosphate during bacterial cell wall assembly (Fig. S1) (10, 11). The uracil-ribose moiety is a key determinant of binding to the MraY target (10).We have begun to focus on the biosynthesis of pacidamycin family uridyl peptide antibiotics due to their three unusual structural features (Fig. 1). The first one is the presence of the nonproteinogenic amino acids L-meta-tyrosine (L-m-Tyr) and DABA, which suggests that nonribosomal peptide synthetase (NRPS) modules might be involved in the tetra/pentapeptide framework formation. The second feature is that the peptide chain direction reverses twice during assembly. As exemplified in pacidamycin 1, the peptide bond between m-Tyr 2 and DABA 3 is a β-rather than an α-peptide linkage. Consequently, the DABA 3 -Ala 4 peptide bond uses the α-amino of DABA moiety and the chain is reversed at Ala 4 . Next, the attachment of that Al...

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confidence: 90%

Identification of the biosynthetic gene cluster for the pacidamycin group of peptidyl nucleoside antibiotics

Zhang

Ostash

Walsh³

2010

Proc. Natl. Acad. Sci. U.S.A.

109

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“…Most of them are also natural products containing a nucleoside moiety and have unique spectra of antimicrobial activity. In recent reports, some synthesized analogues of pacidamycins [27], liposidomycins [28], capuramycin [29,30] and caprazamycins [31,32] showed broader spectrum and more potent antimicrobial activity.…”

Section: Discussionmentioning

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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“…SQ-641 is a potent anti-TB candidate identified from a library of w7000 analogues of capuramycin created by Daiichi-Sankyo (Japan), and targets translocase I (TL1) with potent bactericidal activity against mycobacteria (Hotoda et al, 2003;Koga et al, 2004). Translocase I is an essential enzyme for the biosynthesis of the bacterial cell wall.…”

Section: Sq-641mentioning

confidence: 99%

Challenges facing the drug discovery pipeline for non-tuberculous mycobacteria

Soni

Groote

Dasgupta

et al. 2016

Journal of Medical Microbiology

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Synthesis and Antimycobacterial Activity of Capuramycin Analogues. Part 1. Substitution of the Azepan‐2‐one Moiety of Capuramycin.

Abstract: For Abstract see ChemInform Abstract in Full Text.

Cited by 10 publications

References 1 publication

Identification of the biosynthetic gene cluster for the pacidamycin group of peptidyl nucleoside antibiotics

Identification of the biosynthetic gene cluster for the pacidamycin group of peptidyl nucleoside antibiotics

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

Challenges facing the drug discovery pipeline for non-tuberculous mycobacteria

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