Small Molecule Inhibitor of Quorum Sensing

描述(申请人提供)：机会人类病原体，铜绿假单胞菌，利用酰基高丝氨酸内酯(acyI-HSL)作为群体感应自动诱导剂来激活许多毒力基因的表达。一些毒力因子对宿主组织直接有毒，而另一些则促进生物膜的形成，从而使附着在这些结构中的有机体对抗生素产生抗药性。这对于囊性纤维化患者来说是一个严重的问题，他们经常患上铜绿假单胞菌的慢性肺部感染，尽管接受了积极的抗生素治疗，但这种感染仍然存在。最近对抗生素耐药细菌选择的关注激发了人们对开发抑制各种细菌中毒力因子产生的新疗法的兴趣。这项应用的目标是开发新的小分子，以抑制铜绿假单胞菌的酰基-HSL群体感应，从而减少毒力因子的产生。具有预期活性的吡喃酮和呋喃酮铅化合物已被鉴定。其他与结构相关的分子将被合成并在体外进行测试。这些检测的结果将揭示哪些化合物是群体感应和毒力因子产生的最有效的抑制剂。还将测试活性化合物对细菌生长的抑制作用。对细菌无毒的药物可能会降低选择耐药细菌变体的可能性。在体外测试中显示出最好活性的药物也将在铜绿假单胞菌肺部感染的简单小鼠模型上进行测试。未来的第二阶段研究将在肺部、脓毒症和烧伤的假单胞菌感染的动物模型中测试主导候选药物。这些研究可能导致开发一种新的抗假单胞菌药物，该药物具有独特的作用机制，可能对感染了抗生素耐药生物的免疫功能受损的患者特别有用。

DESCRIPTION (provided by applicant): The opportunistic human pathogen, Pseudomonas aeruginosa, utilizes acyl-homoserine lactones (acyI-HSL) as quorum sensing autoinducers to activate the expression of numerous virulence genes. Some virulence factors are directly toxic to host tissues while others promote formation of biofilms that then confer resistance to antibiotics in organisms enmeshed in these structures. This is a serious problem for cystic fibrosis patients who often develop chronic lung infections with P. aeruginosa that persist despite aggressive antibiotic therapy. Recent concern for the selection of antibiotic resistant bacteria has stimulated interest in the development of novel therapeutics that inhibit virulence factor production in various kinds of bacteria. The goal of this application is to develop novel small molecules that inhibit acyl-HSL quorum sensing in P. aeruginosa and thereby decrease production of virulence factors. Lead pyrrinone and furanone compounds having the desired activity have already been identified. Additional structurally related molecules will be synthesized and tested in vitro. The results of these assays will reveal which compounds are the most potent inhibitors of quorum sensing and virulence factor production. Active compounds will also be tested for inhibition of bacteria growth. Drugs that are not toxic to the bacteria may decrease the likely-hood for the selection of resistant bacteria variants. Drugs that show the best activity in in vitro assays will also be tested in a simple mouse model of P. aeruginosa lung infection. Future Phase II studies will test the lead drug candidate in animal models of Pseudomonas infection in lung, sepsis and burns. These studies may lead to the development of a new anti-Pseudomonas drug with a unique mechanism of action that may be especially useful for immunocompromised patients infected with antibiotic-resistant organisms.