Novel Dual Acting Antibiotics for Pulmonary Disease

摘要 慢性呼吸道疾病，以呼吸道感染为特征，涉及混合细菌植物群， 持续性嗜酸性炎症，是美国第三大死亡原因， 治疗挑战本申请提出了开发新的吸入治疗剂来治疗哮喘。 慢性肺部疾病的潜在感染和炎症。该化合物系列具有新颖的杀菌 没有抵抗和双重抗炎活性的证据的机制（抑制中性粒细胞迁移， 细胞因子释放）。抗生素活性靶向支气管扩张症中的大多数相关病原体，并增强了 氨基糖苷类（如妥布霉素）对革兰氏阳性菌的活性和多粘菌素（如粘菌素）对 革兰氏阴性用妥布霉素增强提高了对革兰氏阳性持留菌的活性， 生物膜初步的体内安全性研究证明了给药12天后的肺部耐受性 (at有效剂量），以及IV给药。该计划有可能解决一个重大的未满足的问题， 支气管扩张症的需求，并提供新的治疗选择，以应对日益增长的抗生素耐药性的威胁。

ABSTRACT Chronic respiratory disease, hallmarked by recalcitrant airway infection involving mixed bacterial flora combined with persistent neutrophilic inflammation, is the 3rd leading cause of death in the US and remains a significant treatment challenge. This application proposes the development of novel, inhaled therapeutic agents to treat the underlying infection and inflammation in chronic lung diseases. The compound series has a novel bactericidal mechanism without evidence of resistance and dual anti-inflammatory activity (inhibits neutrophil migration and cytokine release). The antibiotic activity targets most relevant pathogens in bronchiectasis and potentiates the activity of aminoglycosides (e.g. tobramycin) for Gram-positive organisms and polymyxins (e.g. Colistin) for Gram-negatives. Potentiation with Tobramycin improves activity against Gram-positive persister bacteria and biofilms. Preliminary in vivo safety studies demonstrated pulmonary tolerability after 12 days of administration (at effective doses), as well as, with IV dosing. This program has the potential to address a significant unmet need in bronchiectasis and provide new treatment options against the growing threat of antibiotic resistance.