von Ambüren Julia, Schreiber Fynn, Fischer Julia, Winter Sandra, van Gumpel Edeltraud, Simonis Alexander, Rybniker Jan
Department I of Internal Medicine, University of Cologne, 50937 Cologne, Germany.
Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany.
Microorganisms. 2020 Jul 22;8(8):1096. doi: 10.3390/microorganisms8081096.
The prevalence of bacterial pathogens being resistant to antibiotic treatment is increasing worldwide, leading to a severe global health challenge. Simultaneously, the development and approval of new antibiotics stagnated in the past decades, leading to an urgent need for novel approaches to avoid the spread of untreatable bacterial infections in the future. We developed a highly comprehensive screening platform based on quantification of pathogen driven host-cell death to detect new anti-virulence drugs targeting () and serovar Typhimurium (T), both known for their emerging antibiotic resistance. By screening over 10,000 small molecules we could identify several substances showing promising effects on and T pathogenicity in our in vitro infection model. Importantly, we could detect compounds potently inhibiting bacteria induced killing of host cells and one novel comipound with impact on the function of the type 3 secretion system (T3SS) of T. Thus, we provide proof of concept data of rapid and feasible medium- to high-throughput drug screening assays targeting virulence mechanisms of two major Gram-negative pathogens.
全球范围内，对抗生素治疗产生耐药性的细菌病原体的流行率正在上升，这给全球健康带来了严峻挑战。与此同时，在过去几十年里，新型抗生素的研发和审批陷入停滞，因此迫切需要新的方法来避免未来无法治疗的细菌感染的传播。我们基于对病原体驱动的宿主细胞死亡进行定量分析，开发了一个高度综合的筛选平台，以检测针对 （） 和鼠伤寒血清型 （T） 的新型抗毒力药物，这两种病原体都以其新出现的抗生素耐药性而闻名。通过筛选一万多种小分子，我们在体外感染模型中鉴定出了几种对 （） 和 T 的致病性有显著影响的物质。重要的是，我们能够检测到有效抑制细菌诱导的宿主细胞杀伤的化合物，以及一种对 T 的3型分泌系统 （T3SS） 功能有影响的新型化合物。因此，我们提供了针对两种主要革兰氏阴性病原体毒力机制的快速且可行的中高通量药物筛选试验的概念验证数据。
