Small Molecule Inhibitor of Quorum Sensing

描述（由申请人提供）：机会性人类病原体，铜绿假单胞菌，利用酰基-高丝氨酸内酯（acyI-HSL）作为群体感应自诱导剂来激活许多毒力基因的表达。一些毒力因子直接对宿主组织产生毒性，而另一些毒力因子促进生物膜的形成，然后使包裹在这些结构中的生物体对抗生素产生耐药性。对于囊性纤维化患者来说，这是一个严重的问题，他们经常发展为铜绿假单胞菌的慢性肺部感染，尽管积极的抗生素治疗仍然存在。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毒力因子产生的新疗法的兴趣。本应用的目标是开发新的小分子，抑制铜绿假单胞菌中酰基- hsl群体感应，从而减少毒力因子的产生。具有预期活性的铅吡啶酮和呋喃酮化合物已经被鉴定出来。其他结构相关的分子将被合成并在体外测试。这些试验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。活性化合物还将测试其对细菌生长的抑制作用。对细菌无毒的药物可能会减少选择耐药细菌变体的可能性。在体外试验中表现出最佳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中进行测试。未来的II期研究将在肺部假单胞菌感染、败血症和烧伤的动物模型中测试主要候选药物。这些研究可能导致开发一种具有独特作用机制的新型抗假单胞菌药物，这可能对感染抗生素耐药生物的免疫功能低下患者特别有用。

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.