SYNTHETIC ANTAGONISTS OF THE PSEUDOMONAS AUTOINDUCER

假单胞菌自诱导剂的合成拮抗剂

• 批准号: 2712395
• 负责人: Toni KLINE
• 金额: $ 10万
• 依托单位: PATHOGENESIS CORPORATION
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-01 至 1999-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2712395
• 关键词: Pseudomonas aeruginosa; antibacterial agents; bacterial cytopathogenic effect; bioassay; chemical structure function; drug design /synthesis /production; drug screening /evaluation; host organism interaction; inhibitor /antagonist; lactones; radionuclides; tautomer; transcription factor; virulence

Pseudomonas aeruginosa persists as a serious pathogen infecting the most seriously ill, including cystic fibrosis patients. The tenacious survival of P. aeruginosa, as well as many others of the highly necrotic and toxic effects from P. aeruginosa infections, rely on exoproducts called virulence factors. Expression of virulence factors is regulated by a quorum-sensing mechanism that deploys these factors only when a sufficient concentration of bacteria can make a concerted attack on the host. A master regulatory transcription factor, LasR, controls a number of the individual genes; LasR is activated by a small molecule autoinducer, N-(3- oxo-dodecanoyl)-L-homoserine lactone (PAI-1). A second regulator/autoinducer complex, RHlR and its cognate agonist N-butyryl-L- homoserine lactone (PAI-2), is also a part of the P. aeruginosa virulence factor cascade. We plan to develop antagonists to PAI-1 and PAI-2 that produce the avirulent condition observed in lasl and rhll mutants. Since modifications of the 3-keto group diminishes Pal-1 activity, we will pursue the hypothesis that the beta-ketoamide structure plays a critical role for the Pseudomonas LasR autoinduce. In Phase 1 we will focus primarily on PAl-1 to determine the tautomeric form of the beta-ketoamide in its bioactive state, and we will put in place the appropriate chemistry and biological assays. Proposed commercial applications: A small-molecule antagonist of the autoinducer would target the destructive virulence factors of Pseudomonas, and be useful in treating nosocomial infections and chronic infections seen in cystic fibrosis patients. It would decrease or abolish the damage done during the early stages of infection, and in all stages, disrupt the formation of the biofilm, thereby rendering the pathogen significantly more vulnerable to antibiotic therapy. The current estimate of suitable cases for such therapy could easily approach 100,000 in the U.S.

铜绿假单胞菌持续作为一种严重的病原体感染最 严重疾病，包括囊性纤维化患者。顽强的生存 铜绿假单胞菌，以及许多其他高度坏死和毒性的 铜绿假单胞菌感染的影响，依赖于外产物，称为 毒力因子毒力因子的表达受一种 一种群体感应机制，只有当足够的 集中的细菌可以对宿主进行协同攻击。一 主调节转录因子LasR控制许多转录因子， 单个基因; LasR被小分子自诱导物N-（3- 氧代-十二烷酰基）-L-高丝氨酸内酯（派-1）。第二 调节物/自诱导物复合物，RH 1 R及其同源激动剂N-丁酰基-L- 高丝氨酸内酯（派-2）也是铜绿假单胞菌毒力的一部分 因子级联 我们计划开发派-1和派-2的拮抗剂， 在LASL和RHLL突变体中观察到无毒力条件。各种改良 的3-酮基减少β-1活性，我们将继续研究 假设β-酮酰胺结构对 假单胞菌LasR自诱导。在第1阶段，我们将主要关注PAI-1 为了确定β-酮酰胺在其生物活性中的互变异构形式， 国家，我们将把适当的化学和生物 测定。 拟议的商业应用： 自诱导物的小分子拮抗剂将靶向 假单胞菌属的破坏性毒力因子，并可用于治疗 囊性纤维化患者的医院感染和慢性感染 患者它将减少或消除早期战争期间造成的损害， 感染的各个阶段，在所有阶段，破坏形成的 生物膜，从而使病原体明显更容易受到 抗生素治疗目前估计的适合此类案件 在美国，这种疗法很容易达到10万例。