A Novel Combination Therapy to Treat Biofilm-based Pneumonia Infections

摘要 支气管扩张症是一种以支气管永久性扩张为特征的肺部病理，与 慢性咳嗽、痰和反复呼吸道感染。囊性纤维化(CF)是最好的治疗之一 了解导致进行性支气管扩张、慢性细菌感染和 过早死亡。非慢性支气管扩张症(NCFB)和慢性支气管炎(CF)的患病率都有所增加，并呈现出 给世界各地的医疗保健系统造成重大负担，估计NCFB的流行率约为213例 每10万人。这些数据表明，34万至52.2万名成年人正在接受治疗 2013年对NCFB进行了诊断，当年新诊断出7万名成年人。Cf，影响全球70,000人。 CFB和NCFB都与细菌生物膜有关，标准抗生素很难清除这些细菌生物膜 居住在Biofilm中的细菌对抗生素的基本抗药性或耐受性增加，通常是水平的1000倍。 浮游生物的对应物。因此，许多基于生物膜的感染，如CFB和NCFB，永远不会 通过抗生素治疗清除，慢性感染现在被认为是一种基于生物film的疾病。发展中 加强抗生素杀菌生物膜能力的新的治疗干预措施将是非常重要的 对预防和解决这些感染具有重要的临床意义。 这一阶段的SBIR建议进行实验，以进一步开发一种新的抗微生物组合疗法 肺内分流治疗CF和NCFB我们之前设计并进行了一次高吞吐量 筛选能增强妥布霉素对铜绿假单胞菌生物被膜杀灭作用的小分子。这一幕引导我们 发现常用的抗菌剂三氯生与妥布霉素联合使用时，会增加 与单独使用任何一种治疗方法相比，生物被膜的根除能力都提高了100倍以上。这一组合也显示出活动 对抗革兰氏阳性生物被膜形成者。基于三氯生的广泛安全性研究和一种可接受的 安全概况，这种组合，直接给药到肺部，具有显著的临床潜力。我们的团队 密歇根州立大学的沃特斯实验室和TSRL临床前加速器将各种 在生物膜形成、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.