title: PAP inhibitor with in vivo efficacy identified by Candida albicans genetic profiling of natural products.
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.
authors.affiliation: Center of Fungal Genetics, Merck Frosst Canada & Co., 225 President Kennedy West, Suite 2550, Montreal, Quebec H2X 3Y8, Canada.
authors.forename: Bo
authors.initials: B
authors.lastname: Jiang
authors.forename: Deming
authors.initials: D
authors.lastname: Xu
authors.forename: John
authors.initials: J
authors.lastname: Allocco
authors.forename: Craig
authors.initials: C
authors.lastname: Parish
authors.forename: John
authors.initials: J
authors.lastname: Davison
authors.forename: Karynn
authors.initials: K
authors.lastname: Veillette
authors.forename: Susan
authors.initials: S
authors.lastname: Sillaots
authors.forename: Wenqi
authors.initials: W
authors.lastname: Hu
authors.forename: Roberto
authors.initials: R
authors.lastname: Rodriguez-Suarez
authors.forename: Steve
authors.initials: S
authors.lastname: Trosok
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.forename: Fariba
authors.initials: F
authors.lastname: Rahkhoodaee
authors.forename: Tara
authors.initials: T
authors.lastname: Ransom
authors.forename: Nick
authors.initials: N
authors.lastname: Martel
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.forename: Daniel
authors.initials: D
authors.lastname: Gauvin
authors.forename: Judyann
authors.initials: J
authors.lastname: Wiltsie
authors.forename: Douglas
authors.initials: D
authors.lastname: Wisniewski
authors.forename: Scott
authors.initials: S
authors.lastname: Salowe
authors.forename: Jennifer Nielsen
authors.initials: JN
authors.lastname: Kahn
authors.forename: Ming-Jo
authors.initials: MJ
authors.lastname: Hsu
authors.forename: Robert
authors.initials: R
authors.lastname: Giacobbe
authors.forename: George
authors.initials: G
authors.lastname: Abruzzo
authors.forename: Amy
authors.initials: A
authors.lastname: Flattery
authors.forename: Charles
authors.initials: C
authors.lastname: Gill
authors.forename: Phil
authors.initials: P
authors.lastname: Youngman
authors.forename: Ken
authors.initials: K
authors.lastname: Wilson
authors.forename: Gerald
authors.initials: G
authors.lastname: Bills
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Platas
authors.forename: Fernando
authors.initials: F
authors.lastname: Pelaez
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Diez
authors.forename: Sarah
authors.initials: S
authors.lastname: Kauffman
authors.forename: Jeff
authors.initials: J
authors.lastname: Becker
authors.forename: Guy
authors.initials: G
authors.lastname: Harris
authors.forename: Paul
authors.initials: P
authors.lastname: Liberator
authors.forename: Terry
authors.initials: T
authors.lastname: Roemer
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D000935:Antifungal Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use*; D001232:Aspergillus fumigatus / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D001688:Biological Products / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use*; D002176:Candida albicans / Q000187:drug effects* / Q000235:genetics* / Q000378:metabolism; D002177:Candidiasis / Q000188:drug therapy / Q000378:metabolism; D045424:Complex Mixtures / Q000494:pharmacology; D003839:Deoxyadenosines / Q000378:metabolism / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D025141:Drug Resistance, Fungal; D005285:Fermentation; D006579:Heterozygote; D051379:Mice; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D009154:Mutation; D026723:Polyadenylation / Q000187:drug effects; D011062:Polynucleotide Adenylyltransferase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D000935:Antifungal Agents; D001688:Biological Products; D045424:Complex Mixtures; D003839:Deoxyadenosines; D012333:RNA, Messenger; D011062:Polynucleotide Adenylyltransferase; C058120:cordycepin