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A marine microbiome antifungal targets urgent-threat drug-resistant fungi

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Science  20 Nov 2020:
Vol. 370, Issue 6519, pp. 974-978
DOI: 10.1126/science.abd6919

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Prospecting for antifungal molecules

Marine bacteria produce a plethora of natural products that often have unusual chemical structures and corresponding reactivity, which sometimes translate into a valuable biological function. Zhang et al. used a metabolomic screen to zero in on microbial strains from the microbiome of a sea squirt that produces a high diversity of chemical structures. They then screened these molecules for inhibition of fungi (see the Perspective by Cowen). A polycyclic molecule dubbed turbinmicin possessed potent antifungal activity against the multidrug-resistant fungal pathogens Candida auris and Aspergillus fumigatus. Preliminary mechanism-of-action and mouse toxicity studies suggest that this molecule works though a fungus-specific pathway and is well tolerated at therapeutic doses.

Science, this issue p. 974; see also p. 906

Abstract

New antifungal drugs are urgently needed to address the emergence and transcontinental spread of fungal infectious diseases, such as pandrug-resistant Candida auris. Leveraging the microbiomes of marine animals and cutting-edge metabolomics and genomic tools, we identified encouraging lead antifungal molecules with in vivo efficacy. The most promising lead, turbinmicin, displays potent in vitro and mouse-model efficacy toward multiple-drug–resistant fungal pathogens, exhibits a wide safety index, and functions through a fungal-specific mode of action, targeting Sec14 of the vesicular trafficking pathway. The efficacy, safety, and mode of action distinct from other antifungal drugs make turbinmicin a highly promising antifungal drug lead to help address devastating global fungal pathogens such as C. auris.

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