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

大多数临床使用的抗生素是由链霉菌属的土壤细菌制成的，是在1940年至1960年之间发现的。在过去的60年里，滥用抗生素导致了广泛的耐药性，一些危及生命的感染已经无法治疗。奥尼尔关于抗菌素耐药性的报告预测，到2050年，它将成为主要的死亡原因(全球每年1000万人)，并建议鼓励早期抗生素的发现。该项目的重点是了解和利用一种保守的信号通路，控制链霉菌物种的抗生素生产。在实验室的条件下，他们只生产大约10%的抗生素，其余的是“神秘的”，这意味着它们是在大自然中制造的，而不是在实验室中制造的。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。抗生素的生产与孢子形成有关，我们已经确定了一个名为MTRA的主调节器来协调这些过程。MTRA抑制抗生素的产生，而MTRA基因的缺失激活了我们所测试的所有链霉菌中隐蔽抗生素的产生。在本项目中，您将分析MTRA的细胞作用，并确定一种在金黄色葡萄球菌MTRA突变体中开启的隐蔽抗生素。

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.