Extracytoplasmic protein folding stress signalling as a target for the development of novel antibiotics

鉴于多重耐药菌株的增加，迫切需要新型抗生素。尽管这种未满足的医疗需求，替代抗生素的开发目前在很大程度上被制药行业忽视。导致这种应用的工作已经表明，细菌HtrA蛋白酶DegS的抑制剂是杀死广泛细菌的合适化合物。丝氨酸蛋白酶DegS是细菌细胞包膜的蛋白质折叠应激反应中的关键参与者。这种调节性蛋白酶感知蛋白质折叠应激，并执行控制约100个应激反应基因的sigma E信号级联的限速步骤。由于DegS即使在最佳实验室条件下也是必不可少的，并且在结构和功能上都得到了很好的研究，因此它代表了开发替代抗生素药物类别的有希望的目标。本申请涉及对先前阐明的DegS抑制剂的彻底表征和改进，以及对用于未来先导化合物开发的其他化合物类别的鉴定。该项目将由来自学术界和工业界的研究人员组成的小组进行，他们具有互补的专门知识。生物学和生物化学将由Ehrmann集团完成，化学和化学生物学由Kaiser集团完成，而药物筛选，大部分物理和药物化学将由工业合作伙伴Lead Discovery Center GmbH完成。

Novel antibiotics are urgently needed given the increased occurrence of multiple drug resistant strains. Despite this unmet medical need, the development of alternative antibiotics is currently largely neglected by the pharmaceutical industry. Work leading to this application has shown that inhibitors of the bacterial HtrA protease DegS are suitable compounds to kill a wide range of bacteria. The serine protease DegS is a key player in the protein folding stress response of bacterial cell envelopes. This regulatory protease senses protein folding stress and performs the rate-limiting step of the sigma E signalling cascade controlling about 100 stress response genes. Since DegS is essential even under optimal laboratory conditions and is structurally and functionally well studied, it represents a promising target for the development of alternative antibiotic drug classes. This application involves the thorough characterisation and improvement of a previously elucidated DegS inhibitor and the identification of additional compound classes for future lead compound development. The project will be carried out by a team of researchers from academia and industry with complementary expertise. Biology and biochemistry will be done by the group of Ehrmann, the chemistry and chemical biology by the group of Kaiser while the drug screening, most of the physical and medicinal chemistry will be performed by the industrial partner Lead Discovery Center GmbH.