Antimitotic Rhizoxin Derivatives from a Cultured Bacterial Endosymbiont of the Rice Pathogenic Fungus Rhizopus microsporus
- 11 August 2006
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of the American Chemical Society
- Vol. 128 (35), 11529-11536
- https://doi.org/10.1021/ja062953o
Abstract
The potent antimitotic polyketide macrolide rhizoxin, the causal agent of rice seedling blight, is not produced by the fungus Rhizopus microsporus, as has been believed for over two decades, but by endosymbiotic bacteria that reside within the fungal mycelium. Here we report the successful isolation and large-scale fermentation of the bacterial endosymbiont (“Burkholderia rhizoxina”) in pure culture, which resulted in a significantly elevated (10× higher) production of antimitotics. In addition to several known rhizoxin derivatives, numerous novel natural and semisynthetic variants were isolated, and their structures were fully elucidated. Cell-based assays as well as tubulin binding experiments revealed that methylated seco-rhizoxin derivatives are 1000−10000 times more active than rhizoxin and thus rank among the most potent antiproliferative agents known to date. Furthermore, more stable didesepoxy rhizoxin analogues were obtained by efficiently inhibiting a putative P-450 monooxygenase involved in macrolide tailoring.Keywords
This publication has 26 references indexed in Scilit:
- A total synthesis of the antitumour macrolide rhizoxin DOrganic & Biomolecular Chemistry, 2005
- Conspirators in blightNature, 2005
- Mutasynthese von Aureonitril, einem Aureothin-Derivat mit signifikant verbesserter zytostatischer AktivitätAngewandte Chemie, 2005
- bryACell Chemical Biology, 2004
- Metabolites from symbiotic bacteriaThis review is dedicated to Professor Axel Zeeck on the occasion of his 65th birthday.Natural Product Reports, 2004
- Approaches to identify, clone, and express symbiont bioactive metabolite genesNatural Product Reports, 2003
- Enantioselective Total Synthesis of the Antitumor Macrolide Rhizoxin DThe Journal of Organic Chemistry, 2003
- PrefaceCurrent Medicinal Chemistry - Anti-Cancer Agents, 2002
- Enantioselective Total Synthesis of DidesepoxyrhizoxinTetrahedron Letters, 1995
- Rhizoxin binding to tubulin at the maytansine-binding siteBiochimica et Biophysica Acta (BBA) - General Subjects, 1987