The Conserved Actinobacterial Two-Component System MtrAB Coordinates Chloramphenicol Production with Sporulation in Streptomyces venezuelae NRRL B-65442.
The Conserved Actinobacterial Two-Component System MtrAB Coordinates Chloramphenicol Production with Sporulation in Streptomyces venezuelae NRRL B-65442.
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DOI：
10.3389/fmicb.2017.01145
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发表时间：
2017
影响因子：
5.2
通讯作者：
Hutchings MI
中科院分区：
文献类型：
--
作者：
Som NF;Heine D;Holmes NA;Munnoch JT;Chandra G;Seipke RF;Hoskisson PA;Wilkinson B;Hutchings MI
链霉菌产生许多次级代谢产物，包括一半的已知抗生素。抗生素的产生通常与孢子形成的开始相协调，但这些过程的交叉调节尚未完全了解。这是重要的，因为大多数链霉菌抗生素在实验室条件下以低水平产生或根本不产生，这使得这些化合物的大规模生产非常具有挑战性。在这里，我们的特点是高度保守的放线菌双组分系统MtrAB在模式生物委内瑞拉链霉菌，并提供证据表明，它协调生产的抗生素氯霉素与孢子形成。已知MtrAB在结核分枝杆菌中协调DNA复制和细胞分裂，其中TB-MtrA对于生存力是必需的，但MtrB是不稳定的。我们删除了S中的mtrB。这导致了代谢组的全球变化，包括氯霉素的组成性、更高水平的生产。我们发现氯霉素在野生型菌株中是可检测到的，但仅在非常低的水平，并且仅在它形成孢子后。ChIP-seq显示，MtrA结合DNA复制和细胞分裂基因以及氯霉素生产所需基因的上游。dnaA、dnaN、oriC和wblE（whiB 1）是两种M中MtrA的DNA结合靶点。结核和S.委内瑞拉。有趣的是，S.中TB-MtrA的过表达以及TB-和Sv-MtrA蛋白功能的获得。委内瑞拉还开始提高氯霉素的产量。考虑到MtrAB的保守性，这些构建体可能是操纵其他丝状放线菌中抗生素生产的有用工具。
Streptomyces bacteria make numerous secondary metabolites, including half of all known antibiotics. Production of antibiotics is usually coordinated with the onset of sporulation but the cross regulation of these processes is not fully understood. This is important because most Streptomyces antibiotics are produced at low levels or not at all under laboratory conditions and this makes large scale production of these compounds very challenging. Here, we characterize the highly conserved actinobacterial two-component system MtrAB in the model organism Streptomyces venezuelae and provide evidence that it coordinates production of the antibiotic chloramphenicol with sporulation. MtrAB are known to coordinate DNA replication and cell division in Mycobacterium tuberculosis where TB-MtrA is essential for viability but MtrB is dispensable. We deleted mtrB in S. venezuelae and this resulted in a global shift in the metabolome, including constitutive, higher-level production of chloramphenicol. We found that chloramphenicol is detectable in the wild-type strain, but only at very low levels and only after it has sporulated. ChIP-seq showed that MtrA binds upstream of DNA replication and cell division genes and genes required for chloramphenicol production. dnaA, dnaN, oriC, and wblE (whiB1) are DNA binding targets for MtrA in both M. tuberculosis and S. venezuelae. Intriguingly, over-expression of TB-MtrA and gain of function TB- and Sv-MtrA proteins in S. venezuelae also switched on higher-level production of chloramphenicol. Given the conservation of MtrAB, these constructs might be useful tools for manipulating antibiotic production in other filamentous actinomycetes.