Repurposing antimalarials for the treatment of NTM infections

重新利用抗疟药治疗 NTM 感染

基本信息

批准号：
10646331
负责人：
Mary Jackson
金额：
$ 66.63万
依托单位：
COLORADO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
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/10646331
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 abscessus Mycobacterium avium Complex Mycobacterium avium-intracellulare Infection Mycobacterium tuberculosis Necrosis Nitric Oxide Oxidation-Reduction Peroxides Pharmaceutical Preparations 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 drug development drug efficacy effective therapy efficacy testing extracellular improved in vivo inhibitor lung hypoxia lung lesion microorganism mouse model mutant non-tuberculosis mycobacteria non-tuberculous mycobacterial infection pathogen pharmacologic response sensor standard of care success tuberculosis treatment

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 abscessus Mycobacterium avium Complex Mycobacterium avium-intracellulare Infection Mycobacterium tuberculosis Necrosis Nitric Oxide Oxidation-Reduction Peroxides Pharmaceutical Preparations 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 drug development drug efficacy effective therapy efficacy testing extracellular improved in vivo inhibitor lung hypoxia lung lesion microorganism mouse model mutant non-tuberculosis mycobacteria non-tuberculous mycobacterial infection pathogen pharmacologic response sensor standard of care success tuberculosis treatment

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项目摘要

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无结支菌分枝杆菌（NTM）感染的患病率腹肌复合物（MABSC）和分枝杆菌综合体（MAC）种类在全球范围内增加，对具有结构性或功能性肺部疾病（例如囊性）的易感人群构成特殊威胁纤维化，慢性阻塞性肺部疾病和支气管扩张。这些的固有顽固性对化学治疗和令人震惊的治疗失败率的病原体对开发更有效的治疗方法。 MABSC和MAC在肉芽肿病变内细胞内和细胞外持续的能力非复制状态可能有助于这些微生物的药物耐受性和治疗失败在长期感染的个体中。进一步加剧了此问题是MABSC和MAC形成的能力在人类肺部感染期间，似乎是遗传编程的生物膜。一个共同的压力通过活化免疫细胞内的细胞内和细胞外NTM，在无血管坏死和案例区域颗粒瘤，微聚集或生物膜内是抑制由O2消耗引起的有氧呼吸或暴露于一氧化氮（NO）和一氧化碳。众所周知，结核分枝杆菌（MTB）可以通过诱导约50个基因的调节，该基因在适应时以非复制状态驱动细菌的进入它的新陈代谢维持能量水平和在没有生存的情况下兼容的氧化还原平衡呼吸。因此，控制该法规表达的调节剂的抑制剂正在积极地寻求缩短结核病治疗和降低复发率的潜力使用标准的抗生素。我们最近的研究表明，MABSC和MAC的直系同源调节剂具有与MTB中类似的功能。 MABSC中该调节剂的遗传和药理破坏导致生物膜形成的抑制在缺氧下降低细菌活力并逆转药物耐受性。最重要的是，两个抑制剂我们确定的MABSC中的调节剂在MABSC感染的小鼠中显示出明显的杀菌活性除了增强合并中使用的护理标准抗生素的活性。由于这两个抑制剂是在临床上使用或在II期临床试验中，他们提供的重新利用机会可能很短通往诊所的途径。这些令人兴奋的发现激发了我们建议彻底提出的赠款申请的提交破译这些抑制剂在治疗和辅助治疗益处的基础机制 MABSC（AIM 1），并确定是否可以将相同的治疗策略应用于MAC（AIM 2）。