-
[show abstract]
[hide abstract]
ABSTRACT: Parnafungins, natural products containing an isoxazolidinone ring, have been isolated from Fusarium larvarum and have been shown to be potent inhibitors of the fungal polyadenosine polymerase. The extraction and analysis of fermentation broths of taxonomically related organisms identified as closely related Fusarium spp. produce not only parnafungin A and B, but also significant quantities of two related components. These members of the paranfungin family of natural products have been isolated and the structure of each has been elucidated. While structurally analogous to parnafungin A, parnafungin C is further elaborated by methylation of a phenolic hydroxyl group, and parnafungin D has both the methyl phenol ether as well as an epoxide in the xanthone ring system. Parnafungin C and D have potent, broad spectrum antifungal activity and also have been shown to target fungal mRNA cleavage and polyadenylation.
Bioorganic & medicinal chemistry letters 01/2009; 19(4):1224-7. · 2.65 Impact Factor
-
Bo Jiang,
Deming Xu,
John Allocco,
Craig Parish,
John Davison,
Karynn Veillette,
Susan Sillaots,
Wenqi Hu,
Roberto Rodriguez-Suarez,
Steve Trosok, [......],
Ken Wilson,
Gerald Bills,
Gonzalo Platas,
Fernando Pelaez,
Maria Teresa Diez,
Sarah Kauffman,
Jeff Becker,
Guy Harris,
Paul Liberator,
Terry Roemer
[show abstract]
[hide abstract]
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.
Chemistry & Biology 05/2008; 15(4):363-74. · 5.83 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: A Candida krusei strain from a patient with acute myelogenous leukemia that displayed reduced susceptibility to echinocandin drugs contained a heterozygous mutation, T2080K, in FKS1. The resulting Phe655-->Cys substitution altered the sensitivity of glucan synthase to echinocandin drugs, consistent with a common mechanism for echinocandin resistance in Candida spp.
Antimicrobial Agents and Chemotherapy 05/2007; 51(5):1876-8. · 4.84 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Caspofungin inhibits synthesis of beta-D-1,3 glucan, essential to cell walls in Candida and Aspergillus spp., but activity against less common molds is largely uncharacterized. We demonstrate that caspofungin inhibits beta-D-1,3 glucan synthesis and reduces in vitro growth of clinical isolates from the genera Alternaria, Curvularia, Scedosporium, Acremonium, Bipolaris, and Trichoderma.
Antimicrobial Agents and Chemotherapy 07/2006; 50(6):2214-6. · 4.84 Impact Factor
