Developing new tools for antibiotic discovery in Streptomyces bacteria (HUTCHINGS_U17DTP)

几乎所有临床使用的抗生素都来源于广泛存在于土壤中的链霉菌的天然产物（NPs）。NP的发现在20世纪50年代中期达到顶峰，但DNA测序的新进展加上抗菌素耐药性（AMR）的惊人上升，使人们在21世纪重新对这些细菌及其抗生素产生了兴趣。我们从基因组测序中得知，绝大多数链霉菌的NPs不是在实验室条件下产生的，我们的工作重点是开发工具来打开这些沉默的途径，促进发现新的抗菌素。我们收集了400多个链霉菌菌株，我们估计超过80%的NP生物合成途径在实验室条件下是沉默的。在这个项目中，成功的候选人将分析我们在链霉菌中发现的一个重要的和保守的调节因子。这种调节因子似乎在这些细菌中协调细胞分裂和抗生素的产生。它结合必需DNA复制和细胞分裂基因的启动子，以及模式生物委内瑞拉螺中32个NP生物合成基因簇中的24个。值得注意的是，它还直接与参与DNA复制和抗生素生产的蛋白质相互作用。通过在委内瑞拉葡萄球菌中许多沉默的NPs（包括抗生素）上增加功能突变开关，人为地激活调节因子。您将研究该蛋白在委内瑞拉葡萄球菌中调节DNA复制、细胞分裂和抗生素生产中的作用，并在我们收集的新型基因组测序链霉菌物种中表达功能蛋白，以了解该蛋白是否可以用作激活沉默和新型抗生素生产的通用工具。

Almost all of the antibiotics in clinical use are derived from the natural products (NPs) of Streptomyces bacteria, which are widespread in soil. NP discovery peaked in the mid 1950s but new advances in DNA sequencing combined with the alarming rise in Antimicrobial Resistance (AMR) has led to renewed interest in these bacteria and their antibiotics in the 21st century. We know from genome sequencing that the vast majority of Streptomyces NPs are not made under laboratory conditions and our work is focused on developing tools to switch on these silent pathways and facilitate the discovery of new antimicrobials. We have assembled a collection of more than 400 Streptomyces strains and we estimate that more than 80% of their NP biosynthesis pathways are silent under laboratory conditions.In this project the successful candidate will analyse an essential and conserved regulator that we discovered in Streptomyces. This regulator appears to coordinate cell division and antibiotic production in these bacteria. It binds to the promoters of essential DNA replication and cell division genes and to 24 of the 32 NP biosynthetic gene clusters in the model organism S. venezuelae. Remarkably it also interacts directly with proteins involved in DNA replication and antibiotic production. Artificially activating the regulator through a gain of function mutation switches on numerous silent NPs in S. venezuelae, including antibiotics. You will examine the role of this protein in regulating DNA replication, cell division and antibiotic production in S. venezuelae and also express gain of function proteins in novel genome sequenced Streptomyces species from our collection to see if this protein can be used as a general tool to activate production of silent and novel antibiotics.