A potent novel analogue of the natural macrolide antibiotic etnangien, a structurally unique RNA polymerase inhibitor from myxobacteria, is reported. It may be readily obtained from fermentation broths of Sorangium cellulosum and shows high antibiotic activity, comparable to that of etnangien. However, it is much more readily available than the notoriously labile authentic natural product itself. Importantly, it is stable under neutral conditions, allowing for elaborate NMR measurements for assignment of the 12 hydroxyl- and methyl-bearing stereogenic centers. The full absolute and relative stereochemistries of these complex polyketides were determined by a combination of extensive high-field NMR studies, including J-based configuration analysis, molecular modeling, and synthetic derivatization in combination with an innovative method based on biosynthetic studies of this polyketide which is also presented here. A first look into the solution conformation and 3D structure of these promising macrolide antibiotics is reported. Finally, the complete biosynthetic gene cluster was analyzed in detail, revealing a highly unusual and complex trans-AT type polyketide biosynthesis, which does not follow colinearity rules, most likely performs programmed iteration as well as module skipping, and exhibits HMG-CoA box-directed methylation.

CitationArchazolid A-15-O--D-glucopyranoside and iso-archazolid B: potent V-ATPase inhibitory polyketides from the myxobacteria Cystobacter violaceus and Archangium

The relative and absolute stereochemistry of the 38-membered myxobacterial polyketide rhizopodin, a potent actin-binding macrolide, was determined by J-based configurational analysis in combination with molecular modeling and chemical derivatization.

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Other bioactive products U 1300 Configurational Assignment of Rhizopodin, an Actin-Binding Macrolide from the Myxobacterium Myxococcus stipitatus. -The relative and absolute stereochemistry of the 38-membered myxobacterial polyketide rhizopodin (I), is determined by J-based configurational analysis in combination with molecular modeling and chemical derivatization. -(HORSTMANN, N.; MENCHE*, D.; Chem. Commun. (Cambridge) 2008, 41, 5173-5175; Abt. Org. Chem., Univ. Heidelberg, D-69120 Heidelberg, Germany; Eng.) -M. Paetzel 12-208