Enniatins from a marine-derived fungus Fusarium sp. inhibit biofilm formation by the pathogenic fungus Candida albicans.

Candidemia is a life-threatening disease common in immunocompromised patients, and is generally caused by the pathogenic fungus Candida albicans. C. albicans can change morphology from yeast to hyphae, forming biofilms on medical devices. Biofilm formation contributes to the virulence and drug tolerance of C. albicans, and thus compounds that suppress this morphological change and biofilm formation are effective for treating and preventing candidemia. Marine organisms produce biologically active and structurally diverse secondary metabolites that are promising lead compounds for treating numerous diseases. In this study, we explored marine-derived fungus metabolites that can inhibit morphological change and biofilm formation by C. albicans. Enniatin B (1), B1 (2), A1 (3), D (4), and E (5), visoltricin (6), ergosterol peroxide (7), 9,11-dehydroergosterol peroxide (8), and 3ß,5α,9α-trihydroxyergosta-7,22-dien-6-one (9) were isolated from the marine-derived fungus Fusarium sp. Compounds 1-5 and 8 exhibited inhibitory activity against hyphal formation by C. albicans, and compounds 1-3 and 8 inhibited biofilm formation by C. albicans. Furthermore, compounds 1-3 decreased cell surface hydrophobicity and expression of the hypha-specific gene HWP1 in C. albicans. Compound 1 was obtained in the highest yield. An in vivo evaluation system using silkworms pierced with polyurethane fibers (a medical device substrate) showed that compound 1 inhibited biofilm formation by C. albicans in vivo. These results indicate that enniatins could be lead compounds for therapeutic agents for biofilm infections by C. albicans.

Inhibition of BACE1 and amyloid ß aggregation by polyketide from Streptomyces sp.

Alzheimer's disease (AD) causes cognitive impairment in the elderly and is a severe problem worldwide. One of the major reasons for the pathogenesis of AD is thought to be due to the accumulation of amyloid beta (Aß) peptides that result in neuronal cell death in the brain. In this study, bioassay-guided fractionation was performed to develop seed compounds for anti-AD drugs that can act as dual inhibitors of BACE1 and Aß aggregation from secondary metabolites produced by Streptomyces sp. To improve the solubility, the crude extracts were methylated with trimethylsilyl (TMS) diazomethane and then purified to yield polyketides 1-5, including the new compound 1. We synthesized the compounds 6 and 7 (original compounds 2 and 3, respectively), and their activities were evaluated. KS-619-1, the demethylated form of 4 and 5, was isolated and evaluated for its inhibitory activity. The IC50 values for BACE1 and Aß aggregation were found to be 0.48 and 1.1 µM, respectively, indicating that KS-619-1 could be a lead compound for the development of therapeutic agents for AD.