A Novel Combination Therapy to Treat Biofilm-based Pneumonia Infections

摘要 支气管扩张是一种以支气管永久性扩张为特征的肺部病理学， 慢性咳嗽、咳痰和反复呼吸道感染。囊性纤维化（CF）是最好的 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的患病率均增加， 对全球医疗保健系统造成重大负担，估计NCFB患病率约为213例 每100，000人。这些数据表明，有34万至52.2万成年人接受了治疗， NCFB在2013年，70，000名成年人被新诊断。CF，影响全球7万人。 CF和NCFB都与细菌生物膜有关，这些生物膜难以用标准抗生素清除， 存在于生物膜中的细菌对抗生素的基础耐药性或耐受性增加，通常是1000倍的水平 他们的对手。因此，许多基于生物膜的感染，如CF和NCFB， 通过抗生素治疗清除，慢性感染现在被认为是一种生物膜疾病。发展中 增强抗生素杀灭生物膜能力的新的治疗干预措施将是非常重要的。 在临床上对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组合治疗方法的实验， 经肺给药治疗CF和NCFB。我们以前设计并进行了高通量的 筛选以鉴定增强妥布霉素杀死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， 生物膜根除超过100倍相比，任何单独的治疗。这种组合也显示出活动 对抗革兰氏阳性生物膜形成者。基于三氯生的广泛安全性研究和可接受的 安全性特征，这种组合，直接输送到肺部，具有显着的临床潜力。我们的团队 密歇根州立大学的沃茨实验室和TSRL临床前加速器汇集了各种 生物膜形成、疗效动物模型、PK/PD研究和产品开发方面的专业知识， 启动与FDA的IND前会议所需的临床前研究。

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.