Adjunct therapeutic potential of a repurposed drug inhibiting Mycobacterium abscessus biofilm formation

摘要 分枝杆菌所致肺部非结核分枝杆菌感染的流行情况 脓肿复合体(MABSC)物种在全球范围内不断增加，并对易感疾病构成特别威胁 有结构性或功能性肺部疾病的个人，如囊性纤维化(CF)、慢性阻塞性 肺部疾病和支气管扩张。这些病原体对化疗药物的内在抗药性 治疗和令人震惊的治疗失败率将高度优先放在开发更有效的药物上 治疗方法正在接近。 虽然已知MABSC在增厚的肺泡壁形成微聚体或生物膜，但呼吸道和 患者的肺空洞，生物被膜形成对MABSC感染和耐药的确切贡献 药物治疗从来没有明确确立过。使用临床批准的药物靶向关键 分枝杆菌进入非复制持续状态所需的转录调控因子(DosRS) 我们最近发现它是MABSC生物膜形成的有效抑制剂，本申请提出 首次确定在标准抗生素方案中添加生物膜抑制剂是否可以改善 解药。这种方法对临床用药的治疗益处的概念验证可能需要很短的时间 去诊所的路线。 目标1将首先测试假设，通过参与诱导一种持续状态来应对 低氧，双组分调节因子DosRS有助于MABSC形成生物膜和发育 新近建立的MABSC感染慢性CF(b-ENaC-TG)小鼠模型的表型药物耐受性 在科罗拉多州立大学。AIM 2将验证DosRS作为生物被膜抑制剂的真正靶点 MABSC.最后，Aim 3将评估这些生物膜抑制剂在MABSC中的辅助治疗潜力。 感染b-ENaC-Tg小鼠。

Abstract The prevalence of pulmonary nontuberculous mycobacterial (NTM) infections caused by Mycobacterium abscessus complex (MABSC) species is increasing worldwide and poses a particular threat to susceptible individuals with structural or functional lung conditions such as cystic fibrosis (CF), chronic obstructive pulmonary disease and bronchiectasis. The intrinsic recalcitrance of these pathogens to chemotherapeutic treatments, and alarming treatment failure rates place a high priority on the development of more effective treatment approaches. Although MABSC is known to form microaggregates or biofilms in the thickened alveolar walls, airways and lung cavity of patients, the precise contribution of biofilm formation to MABSC infection and recalcitrance to drug treatment has never been clearly established. Using clinically approved drugs thought to target a key transcriptional regulator (DosRS) required for mycobacteria to enter a state of non-replicating persistence and which we recently found to be potent inhibitors of MABSC biofilm formation, this application proposes to determine, for the first time, whether adding a biofilm inhibitor to standard antibiotic regimens may improve cure. Proof-of-concept of the therapeutic benefit of this approach with clinically-used drugs could be a short route to the clinic. Aim 1 will first test the hypothesis that, through its involvement in inducing a state of persistence in response to hypoxia, the two-component regulator DosRS contributes to the ability of MABSC to form biofilms and develop phenotypic drug tolerance in a chronic CF (b-ENaC-Tg) mouse model of MABSC infection recently developed at Colorado State University. Aim 2 will validate DosRS as the bona fide target of the biofilm inhibitors in MABSC. Finally, Aim 3 will assess the adjunct therapeutic potential of these biofilm inhibitors in MABSC- infected b-ENaC-Tg mice.