Anti-biofilm agents for treating pulmonary infection in Cystic Fibrosis patients

描述（由申请人提供）：囊性纤维化（CF）是高加索人中最常见的缩短寿命的遗传性疾病，铜绿假单胞菌肺部感染是CF患者死亡的主要原因。感染铜绿假单胞菌的患者的治疗因该生物体的细胞间信号传导系统而变得复杂，该系统调节生物膜形成、毒力基因和抗生素抗性基因如外排泵。这些机制增强了细菌对抗生素和宿主防御的抗性，导致恶性循环，其中身体的免疫系统不断对细菌感染进行无效攻击，导致慢性炎症，组织损伤，最终呼吸衰竭。敏捷科学公司（Agile Sciences，Inc.）已经发现了海绵衍生的海洋天然产物的简单衍生物，其对抑制和分散细菌生物膜具有前所未有的活性。这些“抗菌素”化合物与抗生素协同作用，减少细菌生长，降低抗生素对耐药性细菌的MIC。在初步工作中，微生物素分子已经显示出以下功效：1）在低微摩尔浓度下抑制和分散铜绿假单胞菌的生物膜，以及2）与妥布霉素协同作用以停止铜绿假单胞菌在肉汤培养物中的生长。该提案的目的是评估敏捷科学公司的铅电解质化合物在慢性铜绿假单胞菌感染的体内小鼠模型中的疗效，该模型由查佩尔山的Richard Boucher博士开发。为此，第一期短期信托基金项目的具体目标是：1.对5种化合物进行高级体外研究，为体内研究的先导化合物选择提供信息。2.评价特定目标#1中选择的两种先导化合物在慢性铜绿假单胞菌肺部感染Boucher小鼠模型中的疗效。Laura Guogas博士是一位在囊性纤维化肺病方面具有专业知识的微生物学家，她将领导Agile Sciences的内部工作，并协调一个专家合作团队。体内血小板分子的测试将在共同PI的实验室进行，Richard Boucher博士，医学和囊性纤维化的凯南教授和肺研究和治疗中心主任。Ward Peterson博士将提供关于Cyberyte分子临床前开发的指导，他是一家以前专注于CF治疗的生物技术公司的研究和临床前开发副总裁。敏捷联合创始人Christian Melander博士将提供关于生物分子生物学特性的专业知识。该多学科团队将合作评估Agile的新技术在与CF肺相关的体内条件下减少铜绿假单胞菌增殖的潜力。如果成功开发，我们提出的治疗有可能通过根除慢性细菌感染来调节与CF疾病相关的显著死亡率和发病率。 公共卫生相关性：开发治疗囊性纤维化（CF）的疗法尤其具有挑战性，因为在囊性纤维化患者的肺部形成了称为生物膜的细菌群落。Agile Sciences正在开发既能抑制又能分散细菌生物膜的分子，因此有可能显著提高CF抗生素治疗的有效性。改善CF的治疗有可能延长全球数十万CF患者的预期寿命并改善其生活质量。

DESCRIPTION (provided by applicant): Cystic fibrosis (CF) is the most common life shortening inherited disorder amongst Caucasians, and Pseudomonas aeruginosa pulmonary infections are the leading cause of mortality in CF patients. Treatment of patients infected with P. aeruginosa is complicated by the cell-to-cell signaling systems of this organism, which regulate biofilm formation, virulence genes, and antibiotic resistance genes such as efflux pumps. These mechanisms augment bacterial resistance to both antibiotics and host defense, causing a vicious cycle in which the body's immune system continuously mounts an unproductive assault on bacterial infection, resulting in chronic inflammation, tissue damage, and eventually respiratory failure. The co-founders of Agile Sciences, Inc. have discovered simple derivatives of sponge-derived marine natural products with unprecedented activity toward inhibiting and dispersing bacterial biofilms. These "Agilyte" compounds work synergistically with antibiotics to reduce bacterial growth and lower the MICs of antibiotics toward antibiotic-resistant bacteria. In preliminary work, Agilyte molecules have shown efficacy toward: 1) inhibiting and dispersing biofilms of P. aeruginosa at low-micromolar concentrations and 2) working synergistically with tobramycin to stop growth of P. aeruginosa in broth culture. The goal of this proposal is to assess the efficacy of Agile Sciences' lead Agilyte compounds in an in vivo mouse model of chronic P. aeruginosa infection developed by Dr. Richard Boucher at UNC Chapel Hill. To this end, the Specific Aims of this Phase I STTR Project are: 1. To perform advanced in vitro studies of 5 Agilyte compounds to inform lead compound selection for in vivo studies. 2. To evaluate efficacy of two lead compounds selected in Specific Aim #1 in the Boucher mouse model of chronic P. aeruginosa pulmonary infection. Dr. Laura Guogas, a microbiologist with expertise in cystic fibrosis pulmonary disease, will lead the in-house efforts t Agile Sciences as well as coordinate a team of expert collaborators. Testing of Agilyte molecules in vivo will be conducted in the laboratory of the co-PI, Dr. Richard Boucher, the Kenan Professor of Medicine and Cystic Fibrosis and Pulmonary Research and Treatment Center Director at UNC. Guidance on preclinical development of the Agilyte molecules will be provided by Dr. Ward Peterson, former Vice President of Research and Preclinical Development at Inspire Pharmaceuticals, a biotechnology company formerly focused on CF therapeutics. Agile co-founder Dr. Christian Melander will provide expertise on the biological properties of the Agilyte molecules. This multidisciplinary team will work cooperatively to assess the potential of Agile's novel technology to decrease P. aeruginosa proliferation under in vivo conditions relevant to the CF lung. If successfully developed, our proposed therapeutic has the potential to modulate the significant mortality and morbidity associated with CF disease through the eradication of chronic bacterial infection. PUBLIC HEALTH RELEVANCE: Developing therapeutics to treat cystic fibrosis (CF) is especially challenging due to the formation of communities of bacteria called biofilms in the lungs of cystic fibrosis patients. Agile Sciences is developing molecules that both inhibit and disperse bacterial biofilms and thus have the potential to significantly enhance the effectiveness of antibiotic therapy for CF. An improved treatment for CF has the potential to both extend the life expectancy and improve the quality of life for the hundreds of thousands of individuals worldwide who are living with CF.