PAP inhibitor with in vivo efficacy identified by Candida albicans genetic profiling of natural products.
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.
Jiang
Bo
B
Center of Fungal Genetics, Merck Frosst Canada & Co., 225 President Kennedy West, Suite 2550, Montreal, Quebec H2X 3Y8, Canada.
Xu
Deming
D
Allocco
John
J
Parish
Craig
C
Davison
John
J
Veillette
Karynn
K
Sillaots
Susan
S
Hu
Wenqi
W
Rodriguez-Suarez
Roberto
R
Trosok
Steve
S
Zhang
Li
L
Li
Yang
Y
Rahkhoodaee
Fariba
F
Ransom
Tara
T
Martel
Nick
N
Wang
Hao
H
Gauvin
Daniel
D
Wiltsie
Judyann
J
Wisniewski
Douglas
D
Salowe
Scott
S
Kahn
Jennifer Nielsen
JN
Hsu
Ming-Jo
MJ
Giacobbe
Robert
R
Abruzzo
George
G
Flattery
Amy
A
Gill
Charles
C
Youngman
Phil
P
Wilson
Ken
K
Bills
Gerald
G
Platas
Gonzalo
G
Pelaez
Fernando
F
Diez
Maria Teresa
MT
Kauffman
Sarah
S
Becker
Jeff
J
Harris
Guy
G
Liberator
Paul
P
Roemer
Terry
T
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
D000935:Antifungal Agents; D001688:Biological Products; D045424:Complex Mixtures; D003839:Deoxyadenosines; D012333:RNA, Messenger; D011062:Polynucleotide Adenylyltransferase; C058120:cordycepin