Anti-biofilm agents for treating pulmonary infection in Cystic Fibrosis patients
用于治疗囊性纤维化患者肺部感染的抗生物膜药物
基本信息
- 批准号:8252765
- 负责人:
- 金额:$ 42.82万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-09-30 至 2013-05-31
- 项目状态:已结题
- 来源:
- 关键词:Antibiotic ResistanceAntibiotic TherapyAntibioticsBacteriaBacterial InfectionsBiologicalBiological AvailabilityBiotechnologyCaucasiansCaucasoid RaceCellsChronicClinical Drug DevelopmentCollaborationsCommunitiesConsultationsCystic FibrosisDataDevelopmentDiseaseEffectivenessEvaluationGenesGoalsGrowthHost DefenseHousingImmune systemIn VitroInborn Genetic DiseasesIndividualInfectionInflammationLaboratoriesLactamaseLeadLifeLife ExpectancyLungLung diseasesMeasuresMedicineMicrobial BiofilmsMorbidity - disease rateMucous body substanceMulti-Drug ResistanceNorth CarolinaOrganismPatient CarePatientsPermeabilityPharmacologic SubstancePhasePlayPoriferaPropertyPseudomonas aeruginosaPulmonary Cystic FibrosisQuality of lifeResearchResearch ProposalsRespiratory FailureRoleSafetyScienceSignal TransductionSmall Business Technology Transfer ResearchSystemTechnologyTestingTherapeuticTissuesTobramycinToxic effectUniversitiesUp-RegulationVirulenceWorkairway inflammationassaultbacterial resistancecystic fibrosis mousecystic fibrosis patientscytotoxicityderepressiondrug discoveryefflux pumpextracellulargenotoxicityimprovedin vitro testingin vivoin vivo Modelmarine natural productmortalitymouse modelmultidisciplinarynew technologynovelpathogenphysical propertypre-clinicalpre-clinical researchprofessorresearch studyresistance mechanismtreatment centerward
项目摘要
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.
描述(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这种生物的细胞间信号系统而变得复杂,该系统调节生物膜的形成、毒力基因和抗生素耐药基因,如外排泵。这些机制增强了细菌对抗生素和宿主防御的抵抗力,导致了一个恶性循环,在这个恶性循环中,身体的免疫系统不断地对细菌感染进行无效的攻击,导致慢性炎症、组织损伤,最终导致呼吸衰竭。敏捷科学公司的联合创始人发现了海绵衍生的海洋天然产品的简单衍生物,在抑制和分散细菌生物膜方面具有前所未有的活性。这些“Agilyte”化合物与抗生素协同工作,以减少细菌生长,并降低抗生素对抗生素耐药细菌的MIC。在初步工作中,Agilyte分子在以下方面显示出有效性:1)在低微摩尔浓度下抑制和分散铜绿假单胞菌的生物被膜;2)与妥布霉素协同作用,在肉汤培养中阻止铜绿假单胞菌的生长。该提案的目的是评估Agile Sciences的先导Agilyte化合物在由北卡罗来纳大学教堂山分校的Richard Boucher博士开发的慢性铜绿假单胞菌感染小鼠体内模型中的疗效。为此,这个第一阶段STTR项目的具体目标是:1.进行5个Agilyte化合物的高级体外研究,为体内研究的先导化合物选择提供信息。2.评价1号靶点筛选出的两种先导化合物对小鼠慢性铜绿假单胞菌肺部感染的疗效。Laura Guogas博士是一位在囊性纤维化肺部疾病方面具有专业知识的微生物学家,他将领导雅居乐科学的内部工作,并协调一个专家合作者团队。体内Agilyte分子的测试将在北卡罗来纳大学医学和囊性纤维化凯南教授兼肺研究和治疗中心主任理查德·鲍彻博士的实验室进行。有关Agilyte分子临床前开发的指导将由Inspire制药公司前研究和临床前开发副总裁沃德·彼得森博士提供。Inspire制药公司是一家以前专注于CF疗法的生物技术公司。Agile联合创始人克里斯蒂安·梅兰德博士将提供有关Agilyte分子生物学特性的专业知识。这个多学科团队将合作评估雅居乐的新技术在与肺相关的活体条件下减少铜绿假单胞菌增殖的潜力。如果成功开发,我们提出的治疗方法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,因为囊性纤维化患者的肺中形成了称为生物膜的细菌群落。敏捷科学公司正在开发既能抑制细菌生物被膜又能分散细菌生物膜的分子,从而有可能显著提高CF的抗生素治疗效果。改善对CF的治疗既有可能延长预期寿命,也有可能改善全世界数十万患有CF的人的生活质量。
项目成果
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Laura Michelle Guogas其他文献
Laura Michelle Guogas的其他文献
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