Campafungins: Inhibitors of Candida albicans and Cryptococcus neoformans Hyphal Growth

• Published in: Journal of natural products (Washington, D.C.) Vol. 83; no. 9; pp. 2718 - 2726
• Main Authors: Perlatti, Bruno, Harris, Guy, Nichols, Connie B, Ekanayake, Dulamini I, Alspaugh, J. Andrew, Gloer, James B, Bills, Gerald F
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society and American Society of Pharmacognosy 25-09-2020
• Subjects: Anti-Bacterial Agents - pharmacology; Antifungal Agents - pharmacology; Ascomycota - chemistry; Ascomycota - metabolism; Bacteria - drug effects; Candida albicans - drug effects; Cryptococcus neoformans - drug effects; Cyclic AMP-Dependent Protein Kinases - drug effects; Fermentation; Fungi - drug effects; Hyphae - drug effects; Hyphae - growth & development; Microbial Sensitivity Tests; Molecular Structure; Polyketides - pharmacology; Signal Transduction - drug effects
• ISSN: 0163-3864; 1520-6025; 1520-6025
• DOI: 10.1021/acs.jnatprod.0c00641

Campafungin A is a polyketide that was recognized in the Candida albicans fitness test due to its antiproliferative and antihyphal activity. Its mode of action was hypothesized to involve inhibition of a cAMP-dependent PKA pathway. The originally proposed structure appeared to require a polyketide assembled in a somewhat unusual fashion. However, structural characterization data were never formally published. This background stimulated a reinvestigation in which campafungin A and three closely related minor constituents were purified from fermentations of a strain of the ascomycete fungus Plenodomus enteroleucus. Labeling studies, along with extensive NMR analysis, enabled assignment of a revised structure consistent with conventional polyketide synthetic machinery. The structure elucidation of campafungin A and new analogues encountered in this study, designated here as campafungins B, C, and D, is presented, along with a proposed biosynthetic route. The antimicrobial spectrum was expanded to methicillin-resistant Staphylococcus aureus, Candida tropicalis, Candida glabrata, Cryptococcus neoformans, Aspergillus fumigatus, and Schizosaccharomyces pombe, with MICs ranging as low as 4–8 μg mL–1 in C. neoformans. Mode-of-action studies employing libraries of C. neoformans mutants indicated that multiple pathways were affected, but mutants in PKA/cAMP pathways were unaffected, indicating that the mode of action was distinct from that observed in C. albicans.