neorustmicin-a and rustmicin

Galbonolides A and B are antifungal compounds, which are produced by Streptomyces galbus. A multimodular polyketide synthase (PKS) was predicted to catalyze their biosynthesis, and a methoxymalonyl-acyl carrier protein (methoxymalonyl-ACP) was expected to be involved in the biosynthesis of galbonolide A. Cloning of a methoxymalonyl-ACP biosynthesis locus (galGHIJK) and the flanking regions has revealed that the locus is colocalized with beta-ketoacyl synthase (KAS)-related genes (orf3, 4, and 5), but separated from any multimodular PKS gene cluster in S. galbus. A galI-disruption mutant (SK-galI-5) is unable to produce galbonolide A, but can synthesize galbonolide B, indicating that galGHIJK is involved in the biosynthesis of galbonolide A. A disruption mutant of orf4 is severely impaired in the production of both galbonolides A and B. These results indicate that galGHIJK and the KAS genes are involved in the biosynthesis of galbonolides, although they are not colocalized with a multimodular PKS gene cluster. We further propose that a single galbonolide PKS generates two discrete structures, galbonolides A and B, by alternatively incorporating methoxymalonate and methylmalonate, respectively.

Topics: Acyl Carrier Protein; Antifungal Agents; Biosynthetic Pathways; Cloning, Molecular; Gene Deletion; Gene Order; Lactones; Models, Biological; Multigene Family; Mutagenesis, Insertional; Polyketide Synthases; Streptomyces

A series of novel galbonolide derivatives having a modified methyl enol ether moiety were prepared in total synthetic procedures and evaluated for their in vitro antifungal activities. The antifungal activity was labile to modification of the enol ether functionality and almost all of the modified compounds lacked the activity except for the analogue with an introduction of a methylthio group at the C-6 position, which retained a modest antifungal potency against Cryptococcus neoformans.

Topics: Antifungal Agents; Cryptococcus neoformans; Drug Design; Hexosyltransferases; Lactones

The mode of action of the known antifungal macrolides rustmicin (1) and galbonolide B (2) has been determined to be the inhibition of sphingolipid biosynthesis. A large scale fermentation and isolation process was developed for production of large quantities of rustmicin. New 21-hydroxy derivatives of both compounds were isolated from pilot scale fermentations and were also produced by biotransformation of rustmicin and galbonolide B.

Topics: Antifungal Agents; Candida; Candida albicans; Cryptococcus neoformans; Drug Evaluation, Preclinical; Fermentation; Fungi; Lactones; Microbial Sensitivity Tests; Micromonospora; Molecular Structure; Sphingolipids

Topics: Antifungal Agents; Chromatography, Gel; Chromatography, High Pressure Liquid; Chromatography, Ion Exchange; Fungi; Lactones; Microbial Sensitivity Tests; Species Specificity; Streptomyces; Structure-Activity Relationship

Topics: Antifungal Agents; Bacteria; Chemical Phenomena; Chemistry; Fermentation; Fungi; Lactones; Streptomyces