Multi-level regulation of antibiotic production by the conserved response regulator MtrA

临床上使用的大多数抗生素是由链霉菌属的土壤细菌产生的，发现于1940年至1960年之间。在过去的60年里，抗生素的滥用导致了广泛的耐药性，一些危及生命的感染再也无法治疗。O'Neil关于抗生素耐药性的报告预测，到2050年，抗生素耐药性将成为导致死亡的主要原因（全球每年1000万人），并建议刺激早期抗生素的发现。该项目的重点是了解和利用链霉菌中控制抗生素生产的保守信号通路。他们只有10%的抗生素是在实验室条件下生产的，其余的都是“神秘的”，这意味着它们是在自然界中生产的，而不是在实验室中生产的。如果我们能够理解和操纵控制其产生的信号通路，我们就可以发现许多新的抗生素。抗生素的产生与孢子形成有关，我们已经确定了一种名为MtrA的主调节剂，它协调这些过程。在我们测试的所有链霉菌中，mtrA抑制抗生素的产生，mtrA基因的缺失激活了隐蔽抗生素的产生。在这个项目中，你将分析MtrA的细胞作用，并确定一个隐藏的抗生素在S。委内瑞拉mtrA突变体。

Most antibiotics in clinical use are made by soil bacteria in the genus Streptomyces and were discovered between 1940 and 1960. Misuse of antibiotics over the last 60 years has led to widespread resistance and some life-threatening infections can no longer be treated. The O'Neil report on AntiMicrobial Resistance predicts that it will be the major cause of death (10M a year, worldwide) by 2050 and recommends stimulating early stage antibiotic discovery.This project is focussed on understanding and exploiting a conserved signalling pathway which controls antibiotic production in Streptomyces species. They only make ~10% of their antibiotics under lab conditions and the rest are 'cryptic' which means they are made in nature but not in the lab. If we can understand and manipulate the signalling pathways that control their production we can discover many new antibiotics. Antibiotic production is linked to sporulation and we have identified a master regulator called MtrA which coordinates these processes. MtrA represses antibiotic production and deletion of the mtrA gene activates the production of cryptic antibiotics in all the Streptomyces species we have tested. In this project you will analyse the cellular role of MtrA and identify a cryptic antibiotic switched on in an S. venezuelae mtrA mutant.