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

基本信息

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
项目类别：
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

项目摘要

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病理学，其特征是对支气管的永久解释，与A有关慢性咳嗽，痰液产生和复发性呼吸道感染。囊性纤维化（CF）是最好的之一了解导致进行性支气管扩张，慢性细菌感染和的遗传条件过早死亡。非CF支气管平（NCFB）和CF的患病率都增加并呈现全球医疗保健系统的大量燃烧，估计NCFB的患病率约为213例每10万人。这些数据表明，有340,000至522,000名成年人接受治疗对于NCFB而言，2013年和当年有70,000名成年人被新诊断出来。 CF，全世界有70,000人。 CF和NCFB都与细菌生物膜有关，标准抗生素很难清除居住在生物膜中的细菌具有碱性或对抗生素的耐受性的提高，通常在1000倍的水平下他们的浮游物。因此，许多基于生物膜的感染，例如CF和NCFB，从来都不是通过抗生素疗法清除，慢性感染现在被认为是一种基于生物膜的疾病。发展新的理论干预措施潜在抗生素刻板印象生物膜的能力将是高度的在诊所中有意义，以预防和解决这些感染。这一阶段I SBIR提案实验，以进一步开发一种新型的抗菌组合疗法通过肺部递送对CF和NCFB的处理。我们以前设计并进行了高通量屏幕以鉴定小分子，从而增强铜绿假单胞菌生物膜杀死毒素。这个屏幕引导我们为了发现常用使用的抗菌剂三氯生成与毒素相结合时，会增加与单独的任何一种治疗相比，生物膜放射分配比100倍以上。这种组合还显示了活动针对革兰氏阳性生物膜形成。基于对三氯生的广泛安全研究和可接受的这种组合直接传递到肺部具有巨大的临床潜力。我们的团队密歇根州立大学和TSRL临床前加速器的沃特斯实验室汇集了潜水员生物膜形成，效率动物模型，PK/PD研究和产品开发的专业知识以执行启动与FDA预先开会的临床前研究。