Pacidamycin biosynthesis: Identification and heterologous expression of the first uridyl peptide antibiotic gene cluster

Emma J. Rackham, Sabine Gruschow, Amany E. Ragab, Shilo Dickens, Rebecca J. M. Goss

    Research output: Contribution to journalArticlepeer-review

    69 Citations (Scopus)

    Abstract

    The pacidamycins are antimicrobial nucleoside antibiotics produced by Streptomyces coeruleorubidus that inhibit translocase I, an essential bacterial enzyme yet to be clinically targeted. The novel pacidamycin scaffold is composed of a pseudopeptide backbone linked by a unique exocyclic enamide to an atypical 3'-deoxyuridine nucleoside. In addition, the peptidyl chain undergoes a double inversion caused by the incorporation of a diamino acid residue and a rare internal ureido moiety. The pacidamycin gene cluster was identified and sequenced, thereby providing the first example of a biosynthetic cluster for a member of the uridyl peptide family of antibiotics. Analysis of the 22 ORFs provided an insight into the biosynthesis of the unique structural features of the pacidamycins. Heterologous expression in Streptomyces lividans resulted in the production of pacidamycin D and the newly identified pacidamycin S, thus confirming the identity of the pacidamycin biosynthetic gene cluster. Identification of this cluster will enable the generation of new uridyl peptide antibiotics through combinatorial biosynthesis. The concise cluster will provide a useful model system through which to gain a fundamental understanding of the way in which nonribosomal peptide synthetases interact.
    Original languageEnglish
    Pages (from-to)1700-1709
    Number of pages10
    JournalChemBioChem
    Volume11
    Issue number12
    DOIs
    Publication statusPublished - 27 Jul 2010

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