Molecular mechanisms of inherent drug resistance in non-tuberculous mycobacteria

非结核分枝杆菌固有耐药性的分子机制

• 批准号: 10771645
• 负责人: Jeremy Michael Rock
• 金额: $ 75.97万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-22 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10771645
• 关键词: Anti-Bacterial Agents; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Biological; Cells; Chronic Disease; Clinical; Data; Defect; Development; Drug resistance; Environment; Genes; Genetic; Genetic Screening; Genetic Variation; Goals; Growth; Host Defense; Human; Immune; Infection; Investments; Lung diseases; Lung infections; Measures; Modeling; Molecular; Mutation; Mycobacterium abscessus; Mycobacterium avium Complex; Mycobacterium tuberculosis; Organism; Pathway interactions; Patients; Penetration; Pharmaceutical Preparations; Pharmacotherapy; Phylogenetic Analysis; Population; Predisposition; Resistance; Time; Toxic effect; Treatment Failure; Work; chemical genetics; chronic infection; drug development; genetic approach; inhibitor; mycobacterial; non-tuberculosis mycobacteria; pathogen; resistance mechanism; screening; therapeutic target; tissue culture; tool; treatment response; tuberculosis treatment

Abstract Infections caused by non-tuberculous mycobacteria (NTMs) are substantial clinical problems. The response to therapy is disappointing and the goal for patients with chronic infections is generally to control rather than cure infection. This means extended antibiotic treatment with drugs and associated toxicities that tend to accumulate over time. While there has been considerable investment in developing new antibiotics for the treatment of tuberculosis, caused by the related organism Mycobacterium tuberculosis (Mtb), most of these emergent therapies have little or no activity in NTMs. This has made treatment of the rising number of NTM cases highly problematic. Here we propose to use tools we have recently developed to study NTMs and identify mechanisms to resensitize these pathogens to antibiotics to which they are intrinsically resistant. We will use a new tissue culture model of lung infection together with genetic approaches to find and validate genes and pathways that allow growth inhibition at achievable drug concentrations and/or more rapid killing by existing drugs and advanced antibacterial compounds in Mycobacterium abscessus. We will then explore the underlying biologic mechanisms of sensitization and extend these observations to an even more common cause of human infection, organisms of the Mycobacterium avium complex. Our goal is to determine the therapeutic targets that will best result in bacterial clearance even in the absence of effective host defenses.

抽象的 非结核分枝杆菌（NTM）引起的感染是严重的临床问题。回应 治疗令人失望，慢性感染患者的目标通常是控制而不是治愈 感染。这意味着需要延长抗生素治疗的时间，并且相关的毒性往往会累积 随着时间的推移。尽管在开发用于治疗的新抗生素方面投入了大量资金 结核病，由相关生物结核分枝杆菌 (Mtb) 引起，其中大多数是新出现的 疗法对 NTM 几乎没有活性。这使得对不断增加的 NTM 病例的治疗高度重视 有问题的。在这里，我们建议使用我们最近开发的工具来研究 NTM 并确定机制 使这些病原体对它们本身具有耐药性的抗生素重新敏感。我们将使用新的纸巾 肺部感染的培养模型与遗传方法一起寻找和验证基因和途径 允许在可达到的药物浓度下抑制生长和/或更快速地通过现有药物杀死 脓肿分枝杆菌的先进抗菌化合物。然后我们将探索潜在的生物学 致敏机制并将这些观察结果扩展到人类感染的更常见原因， 鸟分枝杆菌复合体的生物体。我们的目标是确定最有效的治疗靶点 即使在缺乏有效宿主防御的情况下，也会导致细菌清除。