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

摘要 结核分枝杆菌引起的肺部非结核分枝杆菌感染的流行情况 MABSC物种在世界范围内不断增加，对易感物种构成了特别的威胁。 患有结构性或功能性肺病的个体，如囊性纤维化（CF）、慢性阻塞性肺病、慢性肺病 肺部疾病和支气管扩张。这些病原体对化疗药物的内在排斥性 治疗，令人震惊的治疗失败率高度重视发展更有效的治疗方法。 治疗方法。 尽管已知MABSC在增厚的肺泡壁、气道和呼吸道中形成微聚集体或生物膜， 患者的肺腔，生物膜形成对MABSC感染的精确贡献和对MABSC感染的耐受性， 药物治疗从未明确确立。使用临床批准的药物， 转录调节因子（DosRS），其是分枝杆菌进入非复制持续状态所需的， 我们最近发现其是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加入生物膜抑制剂是否可以改善 疗方这种方法与临床使用的药物的治疗益处的概念验证可能是一个短暂的 去诊所的路 目标1将首先检验这一假设，即通过参与诱导一种持续状态， 缺氧时，双组分调节剂DosRS有助于MABSC形成生物膜和发育的能力 最近开发的MABSC感染慢性CF（b-ENaC-Tg）小鼠模型中的表型药物耐受性 在科罗拉多州立大学。目的2将验证DosRS作为生物膜抑制剂的真正靶标， MABSC。最后，目标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.