Mixing and matching genes of marine and terrestrial origin in the biosynthesis of the mupirocin antibiotics.
Mixing and matching genes of marine and terrestrial origin in the biosynthesis of the mupirocin antibiotics.
复制标题
DOI：
10.1039/c9sc06192d
复制
发表时间：
2020-05-09
期刊：
影响因子：
8.4
通讯作者：
Willis CL
中科院分区：
文献类型：
--
作者：
Wang L;Song Z;Race PR;Spencer J;Simpson TJ;Crump MP;Willis CL
随着对聚酮生物合成潜在途径的理解不断加深，以及合成生物学工具箱的不断扩展，合理设计和微调聚酮生物合成机制以生产具有更好性能（如稳定性和/或生物活性）的新化合物成为可能。然而，事实证明，设计硫代氨基酚抗生素的途径具有挑战性。在这里，我们报道了一种产生硫马油醇的海洋假异单胞菌的基因可以在从土壤细菌荧光假单胞菌中合成临床重要的抗生素莫匹罗星的生物合成中以功能形式表达。结果表明，这两种途径采用相同的四氢吡喃（THP）环形成机制，并且酶是交叉相容的。此外，下游加工10,11-环氧树脂和10,11-烯基代谢物的效率是相当的。优化了工程菌株的发酵条件，其中假单体酸A（含10,11-环氧化物）的生产被大量更稳定的假单体酸C（含10,11-烯）所取代，为其发展成为比莫匹罗星更稳定、应用更广泛的抗生素铺平了道路。海洋与陆地相遇的地方：通过即插即用的方法，将来自陆生细菌荧光假单胞菌的莫比罗星生物合成基因簇（BGC）与来自产生硫代氨基酚的海洋菌株的异源基因重新利用。
With growing understanding of the underlying pathways of polyketide biosynthesis, along with the continual expansion of the synthetic biology toolkit, it is becoming possible to rationally engineer and fine-tune the polyketide biosynthetic machinery for production of new compounds with improved properties such as stability and/or bioactivity. However, engineering the pathway to the thiomarinol antibiotics has proved challenging. Here we report that genes from a marine Pseudoalternomonas sp. producing thiomarinol can be expressed in functional form in the biosynthesis of the clinically important antibiotic mupirocin from the soil bacterium Pseudomonas fluorescens. It is revealed that both pathways employ the same unusual mechanism of tetrahydropyran (THP) ring formation and the enzymes are cross compatible. Furthermore, the efficiency of downstream processing of 10,11-epoxy versus 10,11-alkenic metabolites are comparable. Optimisation of the fermentation conditions in an engineered strain in which production of pseudomonic acid A (with the 10,11-epoxide) is replaced by substantial titres of the more stable pseudomonic acid C (with a 10,11-alkene) pave the way for its development as a more stable antibiotic with wider applications than mupirocin. Where the sea meets the land: the mupirocin biosynthetic gene cluster (BGC) from the terrestrial bacterium Pseudomonas fluorescens was repurposed via a plug-and-play approach with heterologous genes from the marine strain that produces thiomarinol.
登录
查看更多内容
影响因子：
14.8
作者：
Hmelo LR;Borlee BR;Almblad H;Love ME;Randall TE;Tseng BS;Lin C;Irie Y;Storek KM;Yang JJ;Siehnel RJ;Howell PL;Singh PK;Tolker-Nielsen T;Parsek MR;Schweizer HP;Harrison JJ
通讯作者：
Harrison JJ
影响因子：
16.6
作者：
Murphy, Annabel C.;Fukuda, Daisuke;Simpson, Thomas J.
通讯作者：
Simpson, Thomas J.
影响因子：
14.8
作者：
Kim E;Moore BS;Yoon YJ
通讯作者：
Yoon YJ
影响因子：
--
作者：
El-Sayed, AK;Hothersall, J;Thomas, CM
通讯作者：
Thomas, CM
影响因子：
3.3
作者：
Mantle, PG;De Langen, M;Teo, VK
通讯作者：
Teo, VK