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. 2014 Oct 20;53(43):11583-6.
doi: 10.1002/anie.201405990. Epub 2014 Sep 4.

Forazoline A: marine-derived polyketide with antifungal in vivo efficacy

Thomas P Wyche  1 , Jeff S Piotrowski, Yanpeng Hou, Doug Braun, Raamesh Deshpande, Sean McIlwain, Irene M Ong, Chad L Myers, Ilia A Guzei, William M Westler, David R Andes, Tim S Bugni
Affiliations

Forazoline A: marine-derived polyketide with antifungal in vivo efficacy

Thomas P Wyche et al. Angew Chem Int Ed Engl. .

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 (13)C-(13)C gCOSY and (13)C-(15)N HMQC NMR data provided the direct carbon-carbon and carbon-nitrogen connectivity, respectively. This approach represents the first example of determining direct (13)C-(15)N 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: NMR spectroscopy; antifungal agents; genomics; natural products; structure elucidation.

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Figures

Figure 1
Figure 1
DFT calculated 13C NMR shifts.
Figure 2
Figure 2
Key ROESY correlations and coupling constants.
Figure 3
Figure 3
Forazoline compromises membrane integrity in a dose dependent manner. Forazoline caused cell permeability after 4h of treatment, and membrane damage increased with the concentration. Amphotericin B (AMB) was included as a positive control which causes cell leakage by binding ergosterol in fungal membranes. (Mean ± S.E.)
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