Sterol Sponge Mechanism Is Conserved for Glycosylated Polyene Macrolides.
Sterol Sponge Mechanism Is Conserved for Glycosylated Polyene Macrolides.
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DOI：
10.1021/acscentsci.1c00148
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发表时间：
2021-05-26
影响因子：
18.2
通讯作者：
Mitchell DA
中科院分区：
文献类型：
--
作者：
Guo X;Zhang J;Li X;Xiao E;Lange JD;Rienstra CM;Burke MD;Mitchell DA
两性霉素样糖基化多烯大环内酯（GPMs）是临床和工业上重要的天然产物家族，但它们发挥其非凡生物活性的机制在半个多世纪以来一直不清楚。两性霉素B发挥杀真菌作用主要是通过自组装成膜外海绵，迅速从真菌膜中提取麦角甾醇，但尚不清楚这种机制是否适用于其他GPMs。利用我们假设代表保守麦角甾醇结合域的高度保守的GPM多烯半粒区域，我们绘制了整个GPM序列功能空间的生物信息学图谱，并将GPM生物合成基因簇（bgc）的数量扩大了10倍。我们进一步利用生物信息学预测和基于四氮的反应性筛选，针对GPM的富电子多烯区域，发现了一类含有甲基四烯和二氧化物的GPM， kinesporicin，并将bgc分配给许多先前报道的成员的新生产者。利用一系列结构多样的已知和新发现的gpm，我们发现甾醇海绵的杀真菌作用机制是保守的。基因组挖掘和化学反应相结合发现了新的抗真菌天然产物。这种糖基化的多烯大环内酯通过麦角甾醇提取具有共同的作用模式。
Amphotericin-like glycosylated polyene macrolides (GPMs) are a clinically and industrially important family of natural products, but the mechanisms by which they exert their extraordinary biological activities have remained unclear for more than half a century. Amphotericin B exerts fungicidal action primarily via self-assembly into an extramembranous sponge that rapidly extracts ergosterol from fungal membranes, but it has remained unclear whether this mechanism is applicable to other GPMs. Using a highly conserved polyene–hemiketal region of GPMs that we hypothesized to represent a conserved ergosterol-binding domain, we bioinformatically mapped the entirety of the GPM sequence-function space and expanded the number of GPM biosynthetic gene clusters (BGCs) by 10-fold. We further leveraged bioinformatic predictions and tetrazine-based reactivity screening targeting the electron-rich polyene region of GPMs to discover a first-in-class methyltetraene- and diepoxide-containing GPM, kineosporicin, and to assign BGCs to many new producers of previously reported members. Leveraging a range of structurally diverse known and newly discovered GPMs, we found that the sterol sponge mechanism of fungicidal action is conserved. A combination of genome-mining and chemical reactivity identified new antifungal natural products. Such glycosylated polyene macrolides share a common mode of action via ergosterol extraction.
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