Abstract
Natural products provide an unparalleled source of chemical scaffolds with diverse biological activities and have profoundly impacted antimicrobial drug discovery. To further explore the full potential of their chemical diversity, we survey natural products for antifungal, target-specific inhibitors by using a chemical-genetic approach adapted to the human fungal pathogen Candida albicans and demonstrate that natural-product fermentation extracts can be mechanistically annotated according to heterozygote strain responses. Applying this approach, we report the discovery and characterization of a natural product, parnafungin, which we demonstrate, by both biochemical and genetic means, to inhibit poly(A) polymerase. Parnafungin displays potent and broad spectrum activity against diverse, clinically relevant fungal pathogens and reduces fungal burden in a murine model of disseminated candidiasis. Thus, mechanism-of-action determination of crude fermentation extracts by chemical-genetic profiling brings a powerful strategy to natural-product-based drug discovery.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Alleles
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Amino Acid Sequence
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Animals
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Antifungal Agents / chemistry
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Antifungal Agents / isolation & purification
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Antifungal Agents / pharmacology*
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Antifungal Agents / therapeutic use*
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Aspergillus fumigatus / drug effects
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Aspergillus fumigatus / growth & development
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Aspergillus fumigatus / metabolism
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Biological Products / chemistry
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Biological Products / isolation & purification
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Biological Products / pharmacology*
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Biological Products / therapeutic use*
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Candida albicans / drug effects*
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Candida albicans / genetics*
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Candida albicans / metabolism
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Candidiasis / drug therapy
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Candidiasis / metabolism
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Complex Mixtures / pharmacology
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Deoxyadenosines / metabolism
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Deoxyadenosines / pharmacology
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Drug Evaluation, Preclinical / methods*
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Drug Resistance, Fungal
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Fermentation
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Heterozygote
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Mice
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Microbial Sensitivity Tests
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Molecular Sequence Data
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Mutation
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Polyadenylation / drug effects
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Polynucleotide Adenylyltransferase / antagonists & inhibitors*
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Polynucleotide Adenylyltransferase / genetics
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Polynucleotide Adenylyltransferase / metabolism
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RNA, Messenger / metabolism
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Saccharomyces cerevisiae / drug effects
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Saccharomyces cerevisiae / metabolism
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Treatment Outcome
Substances
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Antifungal Agents
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Biological Products
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Complex Mixtures
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Deoxyadenosines
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RNA, Messenger
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Polynucleotide Adenylyltransferase
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cordycepin