DsbA inhibitors as potential antimicrobials

传染病是世界范围内死亡和发病的主要原因之一。在过去的二十年里，细菌引起的疾病的发病率急剧增加，旧的病原体重新出现，通常是以更致命的形式出现，新的感染性病原体出现。许多致病微生物对抗生素的抗药性越来越强，因此迫切需要新的治疗靶点。我们将通过靶向DsbA来开发新的抗微生物化疗药物，DsbA是一种参与细菌毒力产生的特定因子。这种蛋白存在于大多数细菌中，通过促进毒素和毒力因子的形成而促进致病性。我们将使用基于结构的方法设计特定的DsbA抑制剂，实现基于片断的结晶学和核磁共振铅发现的前沿技术。然后，我们将优化这些片段以开发先导化合物，并通过体外和体内试验评估它们作为DsbA抑制剂的适用性。

Infectious diseases are one of the leading causes of death and morbidity worldwide. In the last two decades the incidence of diseases caused by bacteria has increased dramatically with old pathogens re-emerging, often in a more virulent form, and new infectious agents appearing. Many pathogenic microbes are becoming increasingly resistant to antibiotics so that the need for new therapeutic targets is urgent. We will develop new antimicrobial chemotherapies by targeting DsbA, a specific factor involved in the generation of bacterial virulence. This protein is found in most bacteria and contributes to pathogenicity by promoting the formation of toxins and virulence factors. We will design specific inhibitors of DsbA by using a structure-based approach, implementing the leading edge technologies of fragment-based lead discovery by crystallography and NMR. We will then optimise the fragments to develop lead compounds and evaluate their suitability as DsbA inhibitors by in vitro and in vivo assays.