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Forazoline A: Marine‐Derived Polyketide with Antifungal In Vivo Efficacy |
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| Authors: | Thomas P. Wyche Dr. Jeff S. Piotrowski Dr. Yanpeng Hou Doug Braun Raamesh Deshpande Sean McIlwain Irene M. Ong Chad L. Myers Dr. Ilia A. Guzei Dr. William M. Westler Prof. Dr. David R. Andes Prof. Dr. Tim S. Bugni |
| Affiliation: | 1. Pharmaceutical Sciences Division, University of Wisconsin‐Madison, Madison, WI 53705 (USA);2. Great Lakes Bioenergy Research Center, University of Wisconsin‐Madison, Madison, WI 53726 (USA);3. Department of Computer Science and Engineering, University of Minnesota‐Twin Cities, Minneapolis, MN 55455 (USA);4. Department of Chemistry, University of Wisconsin‐Madison, Madison, WI 53706 (USA);5. Department of Biochemistry, University of Wisconsin‐Madison, Madison, WI 53706 (USA);6. School of Medicine, University of Wisconsin‐Madison, Madison, WI 53705 (USA) |
| Abstract: | Forazoline A, a novel antifungal polyketide with in vivo efficacy against Candida albicans, was discovered using LCMS‐based metabolomics to investigate marine‐invertebrate‐associated bacteria. Forazoline A had a highly unusual and unprecedented skeleton. Acquisition of 13C–13C gCOSY and 13C–15N HMQC NMR data provided the direct carbon–carbon and carbon–nitrogen connectivity, respectively. This approach represents the first example of determining direct 13C–15N connectivity for a natural product. Using yeast chemical genomics, we propose that forazoline A operated through a new mechanism of action with a phenotypic outcome of disrupting membrane integrity. |
| Keywords: | antifungal agents genomics natural products NMR spectroscopy structure elucidation |