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

由于多重耐药菌株的增加，迫切需要新的抗生素。尽管有这种未得到满足的医疗需求，但替代抗生素的开发目前在很大程度上被制药行业忽视了。导致这一应用的工作表明，细菌HtrA蛋白酶的抑制剂是杀死广泛细菌的合适化合物。丝氨酸蛋白酶DEGS在细菌细胞被膜的蛋白质折叠应激反应中起关键作用。这种调节蛋白水解酶感应蛋白质折叠压力，并执行Sigma E信号级联的限速步骤，控制大约100个应激反应基因。由于DEGS即使在最佳的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，因此它是开发替代抗生素药物类别的一个有前途的目标。这项应用包括对先前阐明的DEGS抑制剂的彻底表征和改进，以及为未来的先导化合物开发确定额外的化合物类别。该项目将由一组来自学术界和工业界的研究人员进行，他们拥有互补的专业知识。生物和生物化学将由Ehrmann小组完成，化学和化学生物学将由Kaiser小组完成，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执行。

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.