Brevianes Revisited

Breviones are a new family of secondary metabolites that were originally isolated from the New Zealand endemic fungus Penicillium brevicompactum var. Dierckx. These compounds are generally characterized by a new carbon skeleton, known as breviane, which that has three possible structural variations, such as breviane, abeo-breviane, and abeo-norbreviane. Brevianes present a basic diterpenic tricyclic core that is mevalonic in origin and is similar to that of perhydrophenanthrene. The core bears four methyl groups at positions C4, C8, C10, and C13 and has defined stereochemistry at positions C5, C8, C9, C10, and C14. The C1'-C7' side chain has been proposed to have a polyketide biosynthetic origin and is joined to the diterpenic moiety through carbons C2'-C15'. The cyclization and lactonization of this part of the molecule leads to the characteristic breviane spiranic ring fused to the α-pyrone

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

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 – nonribosomal peptide synthetase, along with enzymes responsible for the biosynthesis of the unusual aminomalonyl-ACP 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