Screening For Inhibitors of Bacterial Capsule Biogenesis

描述(申请人提供)：大肠杆菌对抗生素的耐药性不断上升，这是尿路感染的主要原因，也是败血症-脑膜炎的主要原因，正在推动对新的治疗靶点和这些靶点的化学抑制剂的寻找。抗毒力药物作为化疗药物具有吸引力，可在疾病期间减弱有机体，但不一定具有共生性，从而降低产生耐药性的风险。我们的研究和其他研究表明，E.Coli K胶囊是尿路感染的关键毒力因子。在引起尿路感染的大肠杆菌中K胶囊的组装和出口中所涉及的通路的保守，以及在其他细菌病原体中的相关胶囊的保守使这些通路成为有吸引力的治疗靶点。基于先前建立的Z‘因子为0.93的高通量筛选试验，我们将确定K1胶囊生物发生的抑制剂，K1胶囊是引起UTI的大肠杆菌中最主要的胶囊类型。随后，我们将重点放在一系列领先的抑制剂上，并进行二次检测，以确定抑制的特异性，确定受影响的胶囊类型，并定位目标分子。到项目结束时，我们将有一系列的胶囊生物发生抑制剂，这将促进胶囊生物发生的分子解剖，并可能形成一类新的抗感染药物的基础。 与公共卫生相关：抗生素耐药性持续上升，并正在危及对大肠杆菌感染的治疗，特别是社区获得性尿路感染。K衣壳是重要的大肠杆菌毒力因子。胶囊抑制药物的开发将是抗感染治疗的重要补充。

DESCRIPTION (provided by applicant): Rising antibiotic resistance among Escherichia coli, the leading cause of urinary tract infections and a leading cause of sepsis-meningitis, is driving the search for new therapeutic targets and chemical inhibitors of those targets. Anti-virulence agents are attractive as chemotherapeutics to attenuate an organism during disease but not necessarily commensalism, reducing the risk of developing resistance. Our studies and others have demonstrated that the E. coli K capsule is a critical virulence factor in urinary tract infections. The conservation of pathways involved in the assembly and export of K capsules in UTI-causing E. coli and related capsules in other bacterial pathogens makes these pathways attractive therapeutic targets. Based on the prior development of a high-throughput screening assay with a Z' factor of 0.93, we will identify inhibitors of the biogenesis of the K1 capsule, the leading capsule type among UTI-causing E. coli. Subsequently, we will focus on a leading set of inhibitors and will perform secondary assays to determine the specificity of the inhibition, to ascertain the capsule types that are affected, and to localize the target molecule. By the end of the project, we will have a series of inhibitors of capsule biogenesis that will facilitate the molecular dissection of capsule biogenesis and may form the basis for a new class of anti-infective agents. PUBLIC HEALTH RELEVANCE: Antibiotic resistance continues to rise and is compromising treatment of E. coli infections, particularly community-acquired UTI. K capsule is an important E. coli virulence factor. The development of capsule inhibitory drugs would be an important addition to anti-infective therapies.