Campafungins: Inhibitors of Candida albicans and Cryptococcus neoformans Hyphal Growth.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Perlatti, B; Harris, G; Nichols, CB; Ekanayake, DI; Alspaugh, JA; Gloer, JB; Bills, GF

Published Date

  • September 25, 2020

Published In

Volume / Issue

  • 83 / 9

Start / End Page

  • 2718 - 2726

PubMed ID

  • 32881504

Pubmed Central ID

  • PMC7530089

Electronic International Standard Serial Number (EISSN)

  • 1520-6025

Digital Object Identifier (DOI)

  • 10.1021/acs.jnatprod.0c00641

Language

  • eng

Conference Location

  • United States