Journal article
Campafungins: Inhibitors of Candida albicans and Cryptococcus neoformans Hyphal Growth
Journal of natural products (Washington, D.C.), Vol.83(9), pp.2718-2726
09/25/2020
DOI: 10.1021/acs.jnatprod.0c00641
Abstract
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.
Details
- Title: Subtitle
- Campafungins: Inhibitors of Candida albicans and Cryptococcus neoformans Hyphal Growth
- Creators
- Bruno Perlatti - Texas Therapeutics Institute, The Brown Foundation Institute of Molecular MedicineGuy Harris - Guy Harris ConsultingConnie B Nichols - Departments of Medicine and Molecular Genetics & MicrobiologyDulamini I Ekanayake - Department of ChemistryJ. Andrew Alspaugh - Departments of Medicine and Molecular Genetics & MicrobiologyJames B Gloer - Department of ChemistryGerald F Bills - Texas Therapeutics Institute, The Brown Foundation Institute of Molecular Medicine
- Resource Type
- Journal article
- Publication Details
- Journal of natural products (Washington, D.C.), Vol.83(9), pp.2718-2726
- Publisher
- American Chemical Society and American Society of Pharmacognosy
- DOI
- 10.1021/acs.jnatprod.0c00641
- ISSN
- 0163-3864
- eISSN
- 1520-6025
- Grant note
- DOI: 10.13039/100000060, name: National Institute of Allergy and Infectious Diseases, award: R01AI100272; DOI: 10.13039/100000057, name: National Institute of General Medical Sciences, award: R01GM121458
- Language
- English
- Date published
- 09/25/2020
- Academic Unit
- Chemistry
- Record Identifier
- 9984216579702771
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