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

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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.