Repurposing antimalarials for the treatment of NTM infections

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 结核分枝杆菌复合体（MABSC）和鸟分枝杆菌复合体（MAC）物种在世界范围内增加， 对患有结构性或功能性肺病的易感个体构成特别的威胁， 纤维化、慢性阻塞性肺病和支气管扩张。这些内在的不确定性 病原体对化疗治疗的影响以及令人震惊的治疗失败率， 开发更有效的治疗方法。 MABSC和MAC在肉芽肿性病变中细胞内和细胞外持续存在的能力， 非复制状态可能导致这些微生物的药物耐受性和治疗失败 在慢性感染者身上。进一步使这个问题复杂化的是MABSC和MAC形成 人类肺部感染过程中的生物膜。共同面临的压力 通过激活的免疫细胞内的细胞内和细胞外NTM， 肉芽肿，以及微聚集体或生物膜内是由O2耗尽引起的有氧呼吸抑制 或暴露于一氧化氮（NO）和一氧化碳。M.已知结核病（Mtb）通过以下方式在这种压力下生存下来： 诱导一个约50个基因的调节子，在适应的同时驱动细菌进入非复制状态 它的代谢，以维持能量水平和氧化还原平衡，与生存在缺乏 呼吸因此，控制该调节子表达的调节子的抑制剂正在被积极地研究。 寻求它们在联合使用时缩短结核病治疗和降低复发率的潜力 标准抗生素治疗 我们最近的研究表明，MABSC和MAC的正向调节子发挥与Mtb相似的功能。 MABSC中这种调节剂的遗传和药理学破坏导致生物膜形成的抑制， 降低细菌活力和逆转缺氧下的药物耐受性。最重要的是， 我们鉴定的MABSC中的这种调节剂在MABSC感染的小鼠中显示出显著的杀菌活性， 除了增强联合使用的标准护理抗生素的活性之外。由于这两种抑制剂 无论是临床使用或在第二阶段临床试验，他们提供了重新利用的机会，可能是一个短暂的 去诊所的路 这些令人兴奋的发现促使我们提交了这项赠款申请，我们建议彻底 解释这些抑制剂的治疗和辅助治疗益处的机制， MABSC（目标1），并确定是否可以将相同的治疗策略应用于MAC（目标2）。

Abstract The prevalence of pulmonary nontuberculous mycobacterial (NTM) infections caused by Mycobacterium abscessus complex (MABSC) and Mycobacterium avium complex (MAC) species is increasing worldwide and poses a particular threat to susceptible individuals with structural or functional lung conditions such as cystic fibrosis, 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. The ability of MABSC and MAC to persist intracellularly and extracellularly within granulomatous lesions in a non-replicating state is likely to contribute to the drug tolerance of these microorganisms and to treatment failure in chronically-infected individuals. Further compounding this problem is the ability of MABSC and MAC to form what appears to be genetically programmed biofilms during human pulmonary infections. A common stress faced by intra- and extracellular NTM inside activated immune cells, in avascular necrotic and caseous regions of granulomas, and within microaggregates or biofilms is the inhibition of aerobic respiration caused by O2 depletion or exposure to nitric oxide (NO) and carbon monoxide. M. tuberculosis (Mtb) is known to survive this stress by inducing a regulon of ~50 genes that drives the entry of the bacterium in a non-replicating state while adapting its metabolism to maintain energy levels and a redox balance compatible with survival in the absence of respiration. Accordingly, inhibitors of the regulator which controls the expression of this regulon are actively being sought for their potential to shorten tuberculosis treatment and lower relapse rates when used in combination with standard-of-care antibiotics. Our recent studies indicate that the orthologous regulators of MABSC and MAC play a similar function as in Mtb. Genetic and pharmacological disruption of this regulator in MABSC led to inhibition of biofilm formation in addition to decreasing bacterial viability and reversing drug tolerance under hypoxia. Most importantly, two inhibitors of this regulator in MABSC which we identified showed significant bactericidal activity in MABSC-infected mice in addition to potentiating the activity of standard-of-care antibiotics used in combination. Since these two inhibitors are either clinically-used or in phase II clinical trial, they offer repurposing opportunities that could be a short route to the clinic. These exciting findings stimulated the submission of this grant application in which we propose to thoroughly decipher the mechanisms underlying the therapeutic and adjunct therapeutic benefits of these inhibitors in MABSC (Aim 1) and to determine whether the same therapeutic strategy may be applied to MAC (Aim 2).