Anti-biofilm agents for the treatment of pulmonary infection in cystic fibrosis p

描述(申请人提供)：囊性纤维化(CF)患者死亡的主要原因是肺部感染导致的肺衰竭，而从这些感染中分离出的主要微生物是铜绿假单胞菌。CF患者的肺部感染在患者的一生中持续存在，并且由于细菌形成生物膜和表达多药耐药因素的能力而不可能被根除。生物膜是被保护性基质包围的表面附着的细菌群落。生物膜中的细菌对目前使用的抗菌剂的抗药性是自由漂浮细菌的1000倍以上。除了铜绿假单胞菌形成生物被膜的能力外，已知该细菌还能迅速对抗生素产生抗药性，形成多药耐药(MDR)菌株。由于目前的治疗方法存在固有的局限性，无法有效消除CF患者肺部的铜绿假单胞菌生物被膜和耐多药铜绿假单胞菌，因此需要一种改进的治疗方案来解决这些治疗失败的根本原因。在第一阶段，雅居乐科学公司发现了一种先导2-氨基咪唑(2-AI)化合物AGL-503，该化合物在体外和体内有效地分散多药耐药铜绿假单胞菌生物膜，并通过降低抗生素的MIC值来提高对多药耐药铜绿假单胞菌的抗生素效力。AGL-503是一种有机小分子，通过一种新的作用机制发挥作用，并具有治疗上理想的渗透性、毒性和代谢稳定性特性。此外，在北卡罗来纳大学教堂山分校理查德·鲍彻博士的实验室进行的体内评估中，AGL-503被证明可以破坏小鼠肺内类似生物膜的细菌聚集体。在这一STTR项目的第二阶段，将在目标1中使用药物化学努力，以增强AGL-503的活性。敏捷科学已经组建了一支由微生物学、有机化学、药代动力学/药效学、毒性和临床前开发领域的制药专家组成的团队来指导药物化学计划。目标1中确定的最佳抗生素/2-AI组合将在目标2中使用Boucher博士的小鼠模型进行进一步评估，以最大限度地发挥联合治疗的效果。需要评估的具体变量包括给药途径和给药时间表。马特·沃尔夫冈博士将作为合作研究员加入第二阶段团队，增加铜绿假单胞菌肺部感染模型方面的更多专业知识。在这项工作完成后，敏捷科学公司预计已经确定了候选的2-AI分子，然后将进入临床前开发计划，该计划包括GLP安全评估，以使IND能够提交给FDA和后续的临床试验。在这项第二阶段工作中开发的新疗法有可能大幅提高目前对CF患者肺部顽固性铜绿假单胞菌肺部感染的治疗效果，从而提高这些患者的生活质量和预期寿命。

DESCRIPTION (provided by applicant): The leading cause of mortality in patients with cystic fibrosis (CF) is pulmonary failure from lung infections, and the predominant organism isolated from these infections is the bacterium Pseudomonas aeruginosa. Lung infections of CF patients persist over the lifetime of the patients, and are impossible to eradicate due to the ability of bacteria to form biofilms and to express multidrug resistance elements. Biofilms are surface-attached communities of bacteria that are surrounded by a protective matrix. Bacteria in biofilms are upwards of 1000 times more resistant to currently used antimicrobials than free-floating bacteria. In addition to the ability of P. aeruginosa to form biofilms, the bacterium is known to rapidly acquire resistance to antibiotics to form multidrug resistant (MDR) strains. Due to the inherent limitations of current therapies to effectively eliminate P. aeruginosa biofilms and MDR P. aeruginosa from the lungs of CF patients, an improved therapeutic option is needed that addresses these underlying reasons for treatment failure. In Phase I, Agile Sciences identified a lead 2-aminoimidazole (2-AI) compound, AGL-503, that is effective at dispersing MDR P. aeruginosa biofilms in vitro and in vivo and enhancing antibiotic efficacy toward MDR P. aeruginosa as measured by a lowering of the MIC value of the antibiotic. AGL-503 is a small organic molecule that acts via a novel mechanism of action and possesses therapeutically desirable permeability, toxicity, and metabolic stability properties. Furthermore, in an in vivo evaluation in Dr. Richard Boucher's lab at the University of North Carolina at Chapel Hill, AGL-503 was shown to disrupt biofilm-like aggregates of bacteria within the lungs of mice. In Phase II of this STTR project, a medicinal chemistry effort will be used in Aim 1 to enhance the activity seen with AGL-503. Agile Sciences has assembled a team of pharmaceutical experts in the areas of microbiology, organic chemistry, pharmacokinetics/pharmacodynamics, toxicity, and pre-clinical development to guide the medicinal chemistry program. The optimal antibiotic/2-AI combination identified in Aim 1 will be further evaluated in Aim 2 using Dr. Boucher's murine model to maximize the efficacy of the combination treatment. Specific variables to be evaluated include route of administration as well as dosing schedule. Dr. Matt Wolfgang will join the Phase II team as a co-investigator, adding additional expertise in P. aeruginosa lung infection models. Upon completion of this work, Agile Sciences expects to have identified a candidate 2-AI molecule that will then enter a preclinical development program consisting of GLP safety assessments to enable IND submission to the FDA and subsequent clinical trials. The novel therapy developed in this Phase II work has the potential to substantially enhance current therapeutic performance toward recalcitrant P. aeruginosa lung infections in the lungs of CF patients, thereby increasing the quality of life and life expectancy of these individuals.