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Discovery and Biological Activity of New Chondramides from Chondromyces sp.
MedLine Citation:
PMID:  23959765     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Myxobacteria have proven to be highly valuable sources of natural products, as they produce a variety of secondary metabolites with unique structures and often new modes of action. In this study, high-content screening is demonstrated to be a convenient tool for bioactivity-guided isolation of natural products from crude bacterial extracts. By the application of focused, image-based screens we were able to identify over 30 novel chondramide derivatives from Chondromyces sp. MSr9030, some of which were present in only minute amounts. These cyclic depsipeptides were shown to target actin filaments with a similar binding mode to that of the mushroom toxin phalloidin. Fermentations of the myxobacterial strain were carried out under improved cultivation conditions, and supplementation of the culture broth with potassium bromide afforded the production of brominated analogues that are superior (in terms of biological activity) to all chondramides described to date. Initial biological profiling of 11 new derivatives in comparison to the reference compounds (chondramides A-C) showed that bromo-chondramide C3 and propionyl-bromo-chondramide C3 are the most active in cell-based studies, with GI50 values on human cancer cell lines in the low nanomolar range. Given that these brominated C3 analogues were also less potent on noncancerous human cells (by a factor of 2 to 4 in comparison to cancer cell lines), our results can aid further structure-activity relationship-guided development of chondramides, either as molecular probes or pharmaceutical agents.
Authors:
Jennifer Herrmann; Stephan Hüttel; Rolf Müller
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-8-19
Journal Detail:
Title:  Chembiochem : a European journal of chemical biology     Volume:  -     ISSN:  1439-7633     ISO Abbreviation:  Chembiochem     Publication Date:  2013 Aug 
Date Detail:
Created Date:  2013-8-20     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  100937360     Medline TA:  Chembiochem     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Affiliation:
Microbial Natural Products (MINS), Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI) and Department of Pharmaceutical Biotechnology, Saarland University, Campus C2.3, 66123 Saarbrücken (Germany).
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