Antifungal natural products: Antifungal antimicrobial evaluation of Pseudolarix kaempferi and microbial metabolism of ophiobolin A.

摘要

Bioassay-directed fractionation has resulted in the isolation and identification of a known diterpenoid, pseudolaric acid B, as the major antifungal constituent from the stem and root barks of Pseudolarix kaempferi Gorden, a plant used in Chinese folklore medicine. Pseudolaric acid B possesses strong in vitro activity against fungal pathogens, including Candida albicans, C. parapsilosis, C. tropicalis, Torulopsis petrophilum, T. cremonis, Trichophyton mentagrophytes, and Micosporum gypseum. No antibacterial activity was observed. The minimum inhibitory concentration values of pseudolaric acid B against most of the Candida species are comparable with those of amphotericin B. Methylation or hydrolysis of pseudolaric acid B led to loss of antifungal activity. In a mouse model of disseminated candidiasis, administration of pseudolaric acid B intravenously or subcutaneously could effectively reduce the recovered colony-forming units of C. albicans (p ;Using microbial models of mammalian drug metabolism, the metabolic profile of an antifungal antitumor natural product, ophiobolin A, was evaluated. Starting material ophiobolin A was prepared in gram-scale by fermentation using Cochliobolus heterostrophus. In addition to ophiobolin A, three ophiobolin derivatives, 3-anhydroophiobolin A, ophiobolin B, and ophiobolin L, were isolated from the fermentation broth.;At least seven microorganisms were able to metabolize ophiobolin A after screening 85 organisms. Large scale transformation of ophiobolin A with Polyangium cellulosum produced ophiobolin I and ophiobolin A lactone, and Pseudomonas aeruginosa produced ophiobolin B lactone. Resting-cell preparation of Penicillium patulum afforded 6-epi-ophiobolin A, and 6-epi-ophiobolin L. The structures of these metabolites were established by spectroscopic methods and by comparison of the spectral data with those of the starting material. The antifungal antimicrobial, antiviral activities of the metabolites and the naturally-occurring ophiobolins were also evaluated. The metabolites showed decreased antimicrobial activities against most of the test microorganisms.