oudemansin and mucidin

Topics: Acrylates; Animals; Antifungal Agents; Fatty Acids, Unsaturated; Humans; Methacrylates; Strobilurins; Thiazoles

New antibiotic compounds, melithiazols, were isolated from the culture broth of strains of the myxobacteria Melittangium lichenicola, Archangium gephyra, and Myxococcus stipitatus. The compounds belong to the group of beta-methoxyacrylate (MOA) inhibitors and are related to the myxothiazols. The melithiazols show high antifungal activity, but are less toxic than myxothiazol A and its methyl ester in a growth inhibition assay with mouse cell cultures. The melithiazols inhibit NADH oxidation by submitochondrial particles from beef heart. Melithiazol A blocks the electron transport within the bc1-segment (complex III) and causes a red shift in the reduced spectrum of cytochrome b.

Topics: Acrylates; Animals; Antifungal Agents; Cell Respiration; Cytochrome b Group; Drug Evaluation, Preclinical; Energy Metabolism; Fatty Acids, Unsaturated; Fermentation; Humans; Infant; Inhibitory Concentration 50; Methacrylates; Mice; Microbial Sensitivity Tests; Mitochondria, Heart; Myxococcales; NAD; Strobilurins; Structure-Activity Relationship; Thiazoles

The three E-beta-methoxyacrylate (MOA) inhibitors oudemansin A, strobilurin A and MOA stilbene [3-methoxy-2(2-styrylphenyl)propenic acid-methylester], which differ by more than one order of magnitude in their binding affinity to the mitochondrial ubihydroquinone:cytochrome c oxidoreductase (bc1 complex), bind to a site that is not identical to the binding site for ubihydroquinone, the substrate of the outer ubiquinone reaction site (Qo centre). Although the ubihydroquinone molecule is still bound in the presence of the MOA inhibitors, its electrons cannot be transferred to the iron-sulfur centre. A shift of the relative position of the ubihydroquinone molecule in the reaction centre due to a conformational distortion of cytochrome b induced by the binding of the MOA inhibitor seems to be the reason for the blocked electron transfer. Further analysis shows that ubihydroquinone affects the Kd values of all three MOA inhibitors tested: the values are raised by a constant factor of two, although the inhibitors bind with quite different affinity. The iron-sulfur protein is not involved in the binding of the MOA inhibitors. These results have direct implications for the proper use of MOA inhibitors in experiments designed to analyse the structure/mechanism relationship in cytochrome c reductase. In particular, point mutations recently described in MOA-inhibitor-resistant mutants can no longer be taken to affect necessarily the ubihydroquinone binding site.

Topics: Acrylates; Alkenes; Binding Sites; Cytochrome b Group; Cytochrome Reductases; Energy Transfer; Fatty Acids, Unsaturated; Kinetics; Methacrylates; Mitochondria; NADH Dehydrogenase; Oxidation-Reduction; Oxygen Consumption; Stilbenes; Strobilurins

Topics: Acrylates; Alkenes; Animals; Antifungal Agents; Antimycin A; Cattle; Cytochrome b Group; Cytochromes; Cytochromes c1; Electron Transport; Fatty Acids, Unsaturated; Methacrylates; Spectrum Analysis; Strobilurins; Structure-Activity Relationship; Submitochondrial Particles; Thiazoles; Valerates