A Novel Combination Therapy to Treat Biofilm-based Pneumonia Infections

治疗生物膜肺炎感染的新型联合疗法

• 批准号: 9888308
• 负责人: Elke Lipka
• 金额: $ 27万
• 依托单位: TSRL, INC.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-06 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9888308
• 关键词: Adult; Affect; Age; Animal Model; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Bacteria; Bacterial Infections; Bacteriology; Bronchi; Bronchiectasis; Cessation of life; Chronic; Chronic Obstructive Airway Disease; Clinic; Clinical; Combined Antibiotics; Combined Modality Therapy; Communicable Diseases; Coughing; Coupled; Cystic Fibrosis; Data; Diagnosis; Disease; Dose; Drug Combinations; Drug Kinetics; Economic Burden; Ensure; Evaluation; Exhibits; Formulation; Foundations; Healthcare Systems; Hospitalization; Infection; Inflammation; Inflammatory Response; Inhalation; Inherited; Laboratories; Lead; Length of Stay; Licensing; Lung; Lung diseases; Lung infections; Michigan; Microbe; Microbial Biofilms; Microbiology; Morbidity - disease rate; Mus; Nebulizer; Newly Diagnosed; Outcome; Patients; Persons; Pharmaceutical Preparations; Pharmacodynamics; Phase; Pneumonia; Powder dose form; Premature Mortality; Prevalence; Production; Proton-Motive Force; Pseudomonas aeruginosa; Pulmonary Pathology; Quality of life; Recurrence; Research; Resistance; Respiratory Tract Infections; Safety; Small Business Innovation Research Grant; Sputum; Technology; Therapeutic; Tissues; Tobramycin; Toxic effect; Toxicology; Treatment Efficacy; Treatment outcome; Triclosan; United States; Universities; Water; antibiotic tolerance; antimicrobial; antimicrobial drug; base; chronic infection; clinical development; cost; cystic fibrosis infection; cystic fibrosis patients; design; effective therapy; efflux pump; experience; experimental study; high throughput screening; hospitalization rates; improved; in vitro activity; in vivo; lung basal segment; medication safety; meetings; mortality; novel; novel therapeutic intervention; patient registry; pharmacokinetics and pharmacodynamics; pre-clinical; preclinical efficacy; preclinical study; prevent; product development; pulmonary function; response; safety study; small molecule; survival prediction

Abstract Bronchiectasis is a lung pathology characterized by a permanent dilation of the bronchi and is associated with a chronic cough, sputum production and recurrent respiratory infections. Cystic fibrosis (CF) is one of the best understood inherited conditions that leads to progressive bronchiectasis, chronic bacterial infection and premature mortality. Both non-CF bronchiectasis (NCFB) and CF have increased in prevalence and present a significant burden on healthcare systems worldwide, with an estimated prevalence of NCFB of about 213 cases per 100,000 persons. These data suggest that between 340,000 and 522,000 adults were receiving treatment for NCFB in 2013 and that 70,000 adults were newly diagnosed that year. CF, affects 70,000 people worldwide. Both CF and NCFB are associated with bacterial biofilms, which are difficult to clear with standard antibiotics as bacteria residing in a biofilm have increased basal resistance or tolerance to antibiotics, often at 1000X the level of their planktonic counterparts. Therefore, many biofilm-based infections, such as CF and NCFB, are never cleared by antibiotic therapy, and chronic infections are now recognized as a biofilm-based disease. Developing new therapeutic interventions that potentiate the ability of antibiotics to sterilize biofilms would be highly significant in the clinic to prevent and resolve these infections. This Phase I SBIR proposes experiments to further develop a novel antimicrobial combination therapeutic for the treatment of CF and NCFB by pulmonary delivery. We previously designed and carried out a high-throughput screen to identify small molecules that enhances tobramycin killing of P. aeruginosa biofilms. This screen led us to discover that the commonly used antimicrobial agent triclosan, when combined with tobramycin, increases biofilm eradication by over 100-fold compared to either treatment alone. This combination also shows activity against Gram-positive biofilm formers. Based on the extensive safety studies of triclosan and an acceptable safety profile, this combination, delivered directly to the lung, has significant clinical potential. Our team of the Waters laboratory at Michigan State University and the TSRL Preclinical Accelerator brings together diverse expertise in biofilm formation, animal models of efficacy, PK/PD studies, and product development to perform the pre-clinical studies necessary to initiate a pre-IND meeting with the FDA.

抽象的 支气管扩张是一种肺部病理学，其特征是支气管永久性扩张，并与 慢性咳嗽、咳痰和反复呼吸道感染。囊性纤维化（CF）是最好的治疗方法之一 了解导致进行性支气管扩张、慢性细菌感染和 过早死亡。非 CF 支气管扩张 (NCFB) 和 CF 的患病率均有所增加，并呈现出 NCFB 患病率估计约为 213 例，给全球医疗保健系统带来了沉重负担 每 10 万人。这些数据表明 340,000 至 522,000 名成年人正在接受治疗 2013 年 NCFB 的数据显示，当年新诊断出 70,000 名成年人。 CF，影响全球 70,000 人。 CF 和 NCFB 都与细菌生物膜有关，很难用标准抗生素清除，因为 生物膜中的细菌对抗生素的基础耐药性或耐受性增加，通常达到 1000 倍的水平 他们的浮游对应物。因此，许多基于生物膜的感染，例如 CF 和 NCFB，从未被 通过抗生素治疗可以清除，慢性感染现在被认为是一种基于生物膜的疾病。发展 增强抗生素消毒生物膜能力的新治疗干预措施将非常有效 在临床上预防和解决这些感染具有重要意义。 该 I 期 SBIR 提出了进一步开发新型抗菌联合疗法的实验 通过肺输送治疗 CF 和 NCFB。我们之前设计并进行了高通量 筛选以鉴定增强妥布霉素杀灭铜绿假单胞菌生物膜的小分子。这个屏幕引导我们 发现常用的抗菌剂三氯生与妥布霉素联合使用时，可增加 与单独治疗相比，生物膜根除率超过 100 倍。这种组合也显示出活跃度 对抗革兰氏阳性生物膜形成物。基于三氯生的广泛安全性研究和可接受的 安全性方面，这种直接输送至肺部的组合具有显着的临床潜力。我们的团队 密歇根州立大学沃特世实验室和 TSRL 临床前加速器汇集了不同的 生物膜形成、功效动物模型、PK/PD 研究和产品开发方面的专业知识 与 FDA 启动 IND 前会议所需的临床前研究。