Novel Dual Acting Antibiotics for Pulmonary Disease

摘要 慢性呼吸道疾病，以混合菌群合并顽固性呼吸道感染为特征 持续的中性粒细胞炎症是美国第三大死亡原因，仍然是一个重要的原因 治疗挑战。这一应用促进了新型吸入性治疗剂的开发，以治疗 慢性肺部疾病的潜在感染和炎症。该系列化合物具有一种新型的杀菌作用 没有耐药证据和双重抗炎活性的机制(抑制中性粒细胞迁移和 细胞因子释放)。抗生素活性针对最相关的支扩病原体，并增强 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)对革兰氏阳性菌的活性 革兰氏阴性。妥布霉素增强抗革兰氏阳性耐药菌的活性 生物膜。初步体内安全性研究显示给药12天后肺耐受性良好 (有效剂量)，以及静脉注射剂量。该计划有可能解决一个重大的未满足的问题 在支扩的需求，并提供新的治疗选择，以对抗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.