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 A natural product from a marine bacterium shows selective activity against fungal pathogens. 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.

中文翻译：

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海洋微生物组抗真菌药物针对紧急威胁的耐药真菌

寻找抗真菌分子海洋细菌产生大量天然产物，这些天然产物通常具有不寻常的化学结构和相应的反应性，有时转化为有价值的生物功能。张等人。使用代谢组学筛选将海鞘微生物组中的微生物菌株归零，该微生物组产生高度多样性的化学结构。然后他们筛选了这些分子以抑制真菌（参见 Cowen 的观点）。一种被称为 turbinmicin 的多环分子对多重耐药真菌病原体耳念珠菌和烟曲霉具有有效的抗真菌活性。初步的作用机制和小鼠毒性研究表明，该分子通过真菌特异性途径发挥作用，并且在治疗剂量下具有良好的耐受性。科学，本期第 14 页。974；另见 p. 906 来自海洋细菌的天然产物显示出针对真菌病原体的选择性活性。迫切需要新的抗真菌药物来解决真菌传染病（例如全耐药念珠菌）的出现和跨大陆传播。利用海洋动物的微生物组以及尖端的代谢组学和基因组工具，我们发现了具有体内功效的令人鼓舞的先导抗真菌分子。最有前途的先导药物 turbinmicin 在体外和小鼠模型中对多重耐药真菌病原体表现出强大的功效，表现出广泛的安全指数，并通过真菌特异性作用模式发挥作用，靶向囊泡运输途径的 Sec14。与其他抗真菌药物不同的功效、安全性和作用方式使Turbinmicin成为一种非常有前途的抗真菌药物，有助于解决毁灭性的全球性真菌病原体，例如耳念珠菌。