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

抗生物膜药物治疗囊性纤维化肺部感染

• 批准号: 8775390
• 负责人: Angela Marie Pollard
• 金额: $ 67.28万
• 依托单位: AGILE SCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8775390
• 关键词: Address; Adjuvant; Aerosols; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Area; Back; Bacteria; Biological Assay; Caco-2 Cells; Cells; Clinical; Clinical Trials; Combined Antibiotics; Communities; Cystic Fibrosis; Data; Defense Mechanisms; Development; Dose; Drug Kinetics; Drug resistance; Effectiveness; Elements; Enzymes; Evaluation; Failure; Goals; Immune; In Vitro; Individual; Infection; Infiltration; Lead; Life Expectancy; Lung; Measures; Metabolic; Microbial Biofilms; Microbiology; Minimum Inhibitory Concentration measurement; Modeling; Multi-Drug Resistance; Mus; North Carolina; Organic Chemistry; Organism; Patients; Performance; Permeability; Pharmaceutical Chemistry; Pharmacodynamics; Pharmacologic Substance; Phase; Porifera; Prevalence; Program Development; Property; Pseudomonas aeruginosa; Quality of life; Regimen; Research Personnel; Resistance; Route; Safety; Schedule; Science; Sea; Small Business Technology Transfer Research; Solutions; Sputum; Staging; Structure; Surface; Technology; Testing; Therapeutic; Time; Toxic effect; Treatment Failure; Universities; Work; antimicrobial; cystic fibrosis mouse; cystic fibrosis patients; effective therapy; improved; in vitro Assay; in vivo; intravenous administration; mortality; novel; novel therapeutics; phase 1 study; phase 2 study; pre-clinical; programs; public health relevance; resistant strain; scaffold; signal processing; small molecule; therapy development

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.

描述（由申请人提供）：囊性纤维化患者死亡率（CF）的主要原因是肺部感染引起的肺部衰竭，而从这些感染中分离出的主要有机体是铜绿假单胞菌铜绿细菌。 CF患者的肺部感染在患者的一生中持续存在，由于细菌形成生物膜和表达多药耐药性元件的能力而无法消除。生物膜是被保护基质包围的细菌表面附着的群落。生物膜中的细菌比自由浮动细菌对当前使用的抗菌药物的耐药性高1000倍。除了铜绿假单胞菌形成生物膜的能力外，该细菌还迅速获得对抗生素形成多药耐药性（MDR）菌株的耐药性。由于当前疗法有效地消除了CF患者肺部的铜绿假单胞菌生物膜和MDR P.铜绿假单胞菌的固有局限性，因此需要改进的治疗选择，以解决这些治疗衰竭的基本原因。在第一阶段，敏捷科学鉴定出铅2-氨基咪唑（2-AI）化合物AGL-503，可有效地在体外和体内分散MDR P. eruginosa Biofilms，并增强对MDR P. p. eruginosa的功效，这是通过降低抗伯伯属质子值的降低。 AGL-503是一种小的有机分子，它通过新颖的作用机理起作用，并具有治疗性理想的渗透性，毒性和代谢稳定性。此外，在北卡罗来纳大学教堂山的理查德·鲍彻（Richard Boucher）实验室的体内评估中，AGL-503被证明会破坏小鼠肺中细菌的生物膜样细菌聚集体。在该STTR项目的第二阶段中，将在AIM 1中使用药物化学工作来增强AGL-503所见的活性。敏捷科学已经组建了一支在微生物学，有机化学，药代动力学/药物学，毒性和临床前开发领域的药品专家团队，以指导药物化学计划。 AIM 1中确定的最佳抗生素/2-AI组合将在AIM 2中进一步评估Boucher博士的鼠模型，以最大程度地发挥组合处理的功效。要评估的特定变量包括给药途径和剂量时间表。马特·沃尔夫冈（Matt Wolfgang）博士将加入第二阶段团队，担任共同投资者，并在铜绿假单胞菌肺部感染模型中增加了其他专业知识。这项工作完成后，敏捷科学期望确定一个候选2-AI分子，然后将进入一个由GLP安全评估组成的临床前开发计划，以使IND提交FDA和随后的临床试验。在这一第二阶段的工作中开发的新型疗法有可能大大提高CF患者肺部静脉铜绿假单胞菌肺部感染的当前治疗性能，从而提高这些人的寿命和预期寿命。