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.
Bibliographical noteFunding Information:
We acknowledge financial support from the University of Wisconsin-Madison School of Pharmacy. This work was also funded by the NIH, NIGMS Grant R01 GM092009, and in part by R01 GM104192.
- NMR spectroscopy
- antifungal agents
- natural products
- structure elucidation