Selected Mutations Reveal New Intermediates in the Biosynthesis of Mupirocin and the Thiomarinol Antibiotics
Selected Mutations Reveal New Intermediates in the Biosynthesis of Mupirocin and the Thiomarinol Antibiotics
复制标题
选定的突变揭示了莫匹罗星和硫代马林醇抗生素生物合成中的新中间体
DOI：
10.1002/ange.201611590
复制
发表时间：
2017
影响因子：
--
通讯作者：
Gao S
中科院分区：
文献类型：
--
作者：
Gao S
硫代氨基酚和莫匹罗星组装在相似的聚酮/脂肪酸骨架上，对耐甲氧西林金黄色葡萄球菌（MRSA）表现出强大的抗生素活性。它们都含有对生物活性至关重要的四取代四氢吡喃（THP）环。莫匹罗星是假单胞酸（PAs）的混合物。从ΔmupP菌株中分离出含有7 -羟基- 6 -酮取代THP的新型化合物mupirocin P，化学互补实验证实PA - B转化为主要产物PA - a的第一步是在C6位置氧化。此外，在基因缺失（tmlF）后，分离到9个具有不同氧化模式修饰THP中心核心的新型硫马酚（TM）衍生物。这些代谢物与硫马油醇中THP环的形成和细化一致，遵循与莫匹罗星生物合成相似的顺序，尽管缺乏一些等效基因。利用诱变合成方法合成了新型的莫匹罗辛-硫代马油酚杂合体。
Thiomarinol and mupirocin are assembled on similar polyketide/fatty acid backbones and exhibit potent antibiotic activity against methicillin‐resistant Staphylococcus aureus (MRSA). They both contain a tetrasubstituted tetrahydropyran (THP) ring that is essential for biological activity. Mupirocin is a mixture of pseudomonic acids (PAs). Isolation of the novel compound mupirocin P, which contains a 7‐hydroxy‐6‐keto‐substituted THP, from a ΔmupP strain and chemical complementation experiments confirm that the first step in the conversion of PA‐B into the major product PA‐A is oxidation at the C6 position. In addition, nine novel thiomarinol (TM) derivatives with different oxidation patterns decorating the central THP core were isolated after gene deletion (tmlF). These metabolites are in accord with the THP ring formation and elaboration in thiomarinol following a similar order to that found in mupirocin biosynthesis, despite the lack of some of the equivalent genes. Novel mupirocin–thiomarinol hybrids were also synthesized by mutasynthesis.