Molecular Insights into the Biosynthesis of Guadinomine: A Type III Secretion System Inhibitor

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• 作者：Tracy C. Holmes ; Aaron E. May ; Kathia Zaleta-Rivera ; J. Graham Ruby ; Peter Skewes-Cox ; Michael A. Fischbach ; Joseph L. DeRisi ; Masato Iwatsuki ; Satoshi O虆mura ; Chaitan Khosla
• 刊名：The Journal of the American Chemical Society
• 出版年：2012
• 出版时间：October 24, 2012
• 年：2012
• 卷：134
• 期：42
• 页码：17797-17806
• 全文大小：532K
• 年卷期：v.134,no.42(October 24, 2012)
• ISSN：1520-5126

文摘

Guadinomines are a recently discovered family of anti-infective compounds produced by Streptomyces sp. K01-0509 with a novel mode of action. With an IC₅₀ of 14 nM, guadinomine B is the most potent known inhibitor of the type III secretion system (TTSS) of Gram-negative bacteria. TTSS activity is required for the virulence of many pathogenic Gram-negative bacteria including Escherichia coli, Salmonella spp., Yersinia spp., Chlamydia spp., Vibrio spp., and Pseudomonas spp. The guadinomine (gdn) biosynthetic gene cluster has been cloned and sequenced and includes 26 open reading frames spanning 51.2 kb. It encodes a chimeric multimodular polyketide synthase, a nonribosomal peptide synthetase, along with enzymes responsible for the biosynthesis of the unusual aminomalonyl-acyl carrier protein extender unit and the signature carbamoylated cyclic guanidine. Its identity was established by targeted disruption of the gene cluster as well as by heterologous expression and analysis of key enzymes in the biosynthetic pathway. Identifying the guadinomine gene cluster provides critical insight into the biosynthesis of these scarce but potentially important natural products.