title: Molecular insights into the biosynthesis of guadinomine: a type III secretion system inhibitor.
abstract: Guadinomines are a recently discovered family of anti-infective compounds produced by  Streptomyces  sp. K01-0509 with a novel mode of action. With an IC(50) 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.
authors.affiliation: Department of Chemical Engineering, Stanford University, Stanford, California 94305, USA.
authors.forename: Tracy C
authors.initials: TC
authors.lastname: Holmes
authors.forename: Aaron E
authors.initials: AE
authors.lastname: May
authors.forename: Kathia
authors.initials: K
authors.lastname: Zaleta-Rivera
authors.forename: J Graham
authors.initials: JG
authors.lastname: Ruby
authors.forename: Peter
authors.initials: P
authors.lastname: Skewes-Cox
authors.forename: Michael A
authors.initials: MA
authors.lastname: Fischbach
authors.forename: Joseph L
authors.initials: JL
authors.lastname: DeRisi
authors.forename: Masato
authors.initials: M
authors.lastname: Iwatsuki
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ōmura
authors.forename: Chaitan
authors.initials: C
authors.lastname: Khosla
mesh_terms: D058947:Bacterial Secretion Systems / Q000187:drug effects*; D004151:Dipeptides / Q000096:biosynthesis* / Q000737:chemistry / Q000494:pharmacology*; D048289:Imidazolidines / Q000737:chemistry / Q000494:pharmacology*; D008968:Molecular Conformation; D013302:Streptomyces / Q000737:chemistry / Q000378:metabolism*
chemical_list: D058947:Bacterial Secretion Systems; D004151:Dipeptides; D048289:Imidazolidines; C530703:guadinomine B