Open AccessCampafungins: Inhibitors of Candida albicans and Cryptococcus neoformans Hyphal Growth
Author(s) -
Bruno Perlatti,
Guy H. Harris,
Connie B. Nichols,
Dulamini I. Ekanayake,
J. Andrew Alspaugh,
James B. Gloer,
Gerald F. Bills
Publication year - 2020
Publication title -
journal of natural products
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.976
H-Index - 139
eISSN - 1520-6025
pISSN - 0163-3864
DOI - 10.1021/acs.jnatprod.0c00641
Subject(s) - cryptococcus neoformans , polyketide , candida albicans , aspergillus fumigatus , microbiology and biotechnology , biology , mode of action , candida glabrata , schizosaccharomyces pombe , mutant , corpus albicans , candida tropicalis , stereochemistry , biochemistry , chemistry , enzyme , gene , biosynthesis
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.