Repurposing antimalarials for the treatment of NTM infections

重新利用抗疟药治疗 NTM 感染

• 批准号: 10494711
• 负责人: Mary Jackson
• 金额: $ 64.52万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-15 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10494711
• 关键词: Animal Model; Antibiotics; Antimalarials; Antimycobacterial Agents; Applications Grants; Bacteria; Biological Assay; Bronchiectasis; C3HeB/FeJ Mouse; Carbon Monoxide; Cell Respiration; Cell model; Cells; Chronic; Chronic Obstructive Pulmonary Disease; Clinic; Clinical; Complex; Cystic Fibrosis; Development; Drug Modelings; Drug Targeting; Drug Tolerance; Equilibrium; Exposure to; Genes; Genetic; Genotype; Granuloma; Granulomatous; Heme; Human; Hypoxia; Immune; Immunology; In Vitro; Individual; Infection; Lesion; Lung; Lung infections; Metabolism; Microbial Biofilms; Mus; Mycobacterium Infections; Mycobacterium abscessus; Mycobacterium avium Complex; Mycobacterium avium-intracellulare Infection; Mycobacterium tuberculosis; Necrosis; Nitric Oxide; Oxidation-Reduction; Oxides; Peroxides; Pharmaceutical Preparations; Pharmacology; Phase II Clinical Trials; Phenotype; Phosphotransferases; Physiology; Play; Predisposition; Prevalence; Process; Regimen; Regulon; Relapse; Research Project Grants; Respiration; Route; SCID Mice; Stress; Structure; Testing; Therapeutic; Toxic effect; Treatment Efficacy; Treatment Failure; Treatment outcome; Variant; bactericide; base; drug development; drug efficacy; effective therapy; efficacy testing; extracellular; improved; in vivo; inhibitor; lung hypoxia; lung lesion; microorganism; mouse model; mutant; non-tuberculosis mycobacteria; pathogen; response; sensor; standard of care; success; tuberculosis treatment

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).

抽象的 由分枝杆菌引起的肺部非结核分枝杆菌（NTM）感染的患病率 脓肿复合体 (MABSC) 和鸟分枝杆菌复合体 (MAC) 物种在世界范围内不断增加， 对患有结构性或功能性肺部疾病（例如囊肿）的易感人群构成特别威胁 纤维化、慢性阻塞性肺病和支气管扩张。这些人本质上的顽抗 化疗的病原体和令人震惊的治疗失败率使我们高度重视 开发更有效的治疗方法。 MABSC 和 MAC 在肉芽肿病变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 在慢性感染者中。使这个问题进一步复杂化的是 MABSC 和 MAC 形成的能力 人类肺部感染期间似乎是经过基因编程的生物膜。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，在无血管坏死和干酪样区域 肉芽肿，以及微团聚体或生物膜内，抑制氧气消耗引起的有氧呼吸 或接触一氧化氮 (NO) 和一氧化碳。已知结核分枝杆菌 (Mtb) 可以通过以下方式在这种压力下生存： 诱导大约 50 个基因的调节子，驱动细菌在适应时进入非复制状态 它的新陈代谢可以维持能量水平和氧化还原平衡，从而在没有 呼吸。因此，控制该调节子表达的调节剂抑制剂正在被积极研究。 寻求联合使用时缩短结核病治疗时间并降低复发率的潜力 使用标准护理抗生素。 我们最近的研究表明，MABSC 和 MAC 的直系同源调节因子与 Mtb 中发挥着相似的功能。 MABSC 中该调节剂的遗传和药理学破坏还导致生物膜形成的抑制 降低细菌活力并逆转缺氧条件下的药物耐受性。最重要的是，有两种抑制剂 我们鉴定出的 MABSC 中的这个调节剂在 MABSC 感染的小鼠中表现出显着的杀菌活性 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 无论是临床使用还是处于 II 期临床试验中，它们都提供了可能是短期的再利用机会 前往诊所的路线。 这些令人兴奋的发现促使我们提交了这份赠款申请，我们建议彻底 破译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）。