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

描述（由申请人提供）：囊性纤维化（CF）患者死亡的主要原因是肺部感染引起的肺衰竭，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，并且由于细菌能够形成生物膜和表达多药耐药因子而无法根除。生物膜是表面附着的细菌群落，被保护性基质包围。生物膜中的细菌对目前使用的抗菌剂的耐药性比自由漂浮的细菌高1000倍以上。除了铜绿假单胞菌形成生物膜的能力外，已知该细菌可迅速获得对抗生素的耐药性，形成多重耐药（MDR）菌株。由于目前的治疗方法在有效消除CF患者肺部的铜绿假单胞菌生物膜和耐多药铜绿假单胞菌方面存在固有局限性，因此需要一种改进的治疗方案来解决这些治疗失败的潜在原因。在I期研究中，Agile Sciences发现了一种2-氨基咪唑（2-AI）先导化合物AGL-503，该化合物在体外和体内都能有效分散耐多药铜绿假单胞菌生物膜，并通过降低抗生素的MIC值来提高抗生素对耐多药铜绿假单胞菌的疗效。AGL-503是一种小有机分子，通过一种新的作用机制起作用，具有治疗上理想的渗透性、毒性和代谢稳定性。此外，在北卡罗来纳大学教堂山分校Richard Boucher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部的生物膜样细菌聚集体。在这个STTR项目的第二阶段，药物化学工作将在Aim 1中使用，以增强AGL-503的活性。Agile Sciences已经在微生物学，有机化学，药代动力学/药效学，毒性和临床前开发领域组建了一个药物专家团队来指导药物化学项目。在Aim 1中确定的最佳抗生素/2- ai组合将在Aim 2中使用Dr. Boucher的小鼠模型进一步评估，以最大限度地提高联合治疗的疗效。需要评估的具体变量包括给药途径和给药计划。Matt Wolfgang博士将作为联合研究员加入二期研究团队，增加铜绿假单胞菌肺部感染模型方面的专业知识。这项工作完成后，Agile Sciences预计将确定一个候选2-AI分子，然后进入临床前开发计划，包括GLP安全性评估，以便向FDA提交IND和随后的临床试验。在这项II期研究中开发的新疗法有可能大大提高CF患者肺部难治性铜绿假单胞菌肺部感染的现有治疗效果，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.