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

描述（由申请方提供）：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，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元件的能力而不可能根除。生物膜是由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之外，已知该细菌快速获得对抗生素的抗性以形成多药耐药（MDR）菌株。由于当前疗法从CF患者的肺中有效消除铜绿假单胞菌生物膜和MDR铜绿假单胞菌的固有局限性，需要改进的治疗选择来解决治疗失败的这些根本原因。在I期，Agile Sciences鉴定了一种先导2-氨基咪唑（2-AI）化合物AGL-503，该化合物可有效分散体外和体内MDR铜绿假单胞菌生物膜，并通过降低抗生素的MIC值来增强对MDR铜绿假单胞菌的抗生素疗效。AGL-503是一种小的有机分子，通过一种新的作用机制发挥作用，并具有治疗所需的渗透性、毒性和代谢稳定性。此外，在查佩尔山的北卡罗来纳州大学的Richard Boucher博士实验室的体内评价中，显示AGL-503破坏小鼠肺内细菌的生物膜样聚集体。在该STTR项目的第二阶段，药物化学工作将用于目标1，以增强AGL-503的活性。Agile Sciences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，以指导药物化学项目。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博士的鼠模型进一步评价，以最大限度地提高组合治疗的疗效。待评价的具体变量包括给药途径以及给药方案。Matt Wolfgang博士将作为合作研究者加入II期团队，增加铜绿假单胞菌肺部感染模型的额外专业知识。完成这项工作后，Agile Sciences预计将确定一个候选2-AI分子，然后将进入临床前开发计划，包括GLP安全性评估，以使IND提交给FDA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目前对CF患者肺部中的铜绿假单胞菌肺部感染的治疗性能，从而提高这些个体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.