Role of ribosome modulating proteins in conferring Mycobacterium abscessus antibiotic resistance

核糖体调节蛋白在赋予脓肿分枝杆菌抗生素耐药性中的作用

• 批准号: 10094343
• 负责人: Pallavi Ghosh
• 金额: $ 50.03万
• 依托单位: WADSWORTH CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-21 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10094343
• 关键词: Amikacin; Aminoglycoside resistance; Aminoglycosides; Antibiotic Resistance; Antibiotic susceptibility; Antibiotics; Bacteria; Binding; Binding Proteins; Biochemical; Cefoxitin; Chronic; Collaborations; Cryoelectron Microscopy; Development; Dissociation; Drug resistance; Environment; Exhibits; Exposure to; Genetic; Genomics; Guanosine Triphosphate Phosphohydrolases; Hibernation; Imipenem; In Vitro; Infection; Injectable; Intervention; Lung infections; Macrolides; Mediating; Messenger RNA; Microbial Antibiotic Resistance; Modeling; Molecular; Mycobacterium abscessus; Mycobacterium smegmatis; Mycobacterium tuberculosis; Oral; Pathogenicity; Pathway interactions; Patients; Pharmaceutical Preparations; Population; Proteins; Regimen; Resistance; Ribosomes; Role; Site; Skin Tissue; Soft Tissue Infections; Structure; Tissues; Treatment Efficacy; Work; Y protein; Zinc; Zinc deficiency; drug sensitivity; in vivo; lincosamide; lung injury; mutant; mycobacterial; novel; novel therapeutic intervention; pathogen; resistance mechanism; response; tigecycline

Project Summary: Mycobacterium abscessus (Mab) is a rapidly growing NTM causing skin and soft tissue infections and pulmonary infections in patients with chronic lung damage. It stands apart as one of the most antibiotic resistant microbial species, making its infections incredibly difficult to treat. A combination of an oral macrolide and the aminoglycoside, amikacin, comprises the frontline treatment against Mab. Therapy is prolonged and low cure rates are deplorable. The poor efficacies of these antibiotics result from various mechanisms of intrinsic resistance induced in Mab upon exposure to drugs as well as the host environment. Recently we showed that MabHflX, a conserved ribosome-associated GTPase, is required for macrolide-lincosamide resistance (4). The absence of HflX in a DMs_hflX deletion strain results in an increased population of 70S ribosomes suggesting that HflX is involved in dissociation of ribosomes stalled in the presence of antibiotics. However, the detailed mechanism of HflX-mediated antibiotic resistance, as well as the mechanisms by which antibiotic-bound ribosomal subunits are recycled remain unknown. In another study we demonstrated a role for ARE-ABCF proteins in macrolide/lincosamide resistance. In Aim 1 of this proposal we will use a combination of genetic, biochemical and structural approaches to determine the mechanisms of HflX and ABCF-mediated macrolide-lincosamide resistance. In another independent study, aminoglycoside resistance in zinc-starved M. smegmatis was found to originate from ribosome hibernation, which involves binding of mycobacterial protein Y (MPY). We hypothesize that a low-zinc host environment would similarly result in MPY-dependent ribosome hibernation during Mab infection, and confer resistance to aminoglycosides including amikacin. In Aim 2 of this proposal, we will determine the role of MabMPY in aminoglycoside resistance of which could potentially explain the observed discord between in vitro efficiency and in vivo efficacy of the current treatments (Aim 2). The extreme innate antibiotic resistance of Mab presents a unique opportunity to study the convergence of multiple resistance mechanisms in this pathogen. An in-depth understanding of these various mechanisms is critical in the development of new therapeutic approaches towards treatment of Mab infections.

项目摘要： 分枝杆菌（MAB）是一种快速生长的NTM，引起皮肤和软组织感染 慢性肺损伤患者的肺部感染。它是最抗生素的人之一 抗性微生物物种，使其感染难以治疗。口头的组合 大环内酯类和氨基糖苷Amikacin包括针对MAB的前线治疗。治疗是 延长和低的治疗率是可悲的。这些抗生素的效力不佳来自各种 暴露于药物和宿主时，MAB引起的内在抗性机制以及宿主 环境。 最近，我们表明Mabhflx是一种保守的核糖体相关GTPase，需要 大环内酯类酰胺耐药性（4）。 DMS_HFLX缺失菌株中的HFLX不存在导致 核糖体的种群增加，表明HFLX参与核糖体的解离 在抗生素的情况下。但是，HFLX介导的抗生素耐药性的详细机制为 以及回收抗生素结合的核糖体亚基的机制尚不清楚。在 我们的另一项研究证明了AR-ABCF蛋白在大花环/林果酰胺耐药性中的作用。目标 1本提案中，我们将使用遗传，生化和结构方法的组合来确定 HFLX和ABCF介导的大环内酯酰胺耐药的机理。 在另一项独立研究中，发现锌饥饿的氨基糖苷耐药性。 起源于核糖体冬眠，涉及分枝杆菌蛋白Y（MPY）的结合。我们 假设低锌主机环境类似地导致MPY依赖性核糖体 MAB感染期间的冬眠，并赋予对包括amikacin在内的氨基糖苷的耐药性。在目标2中 在该提案中，我们将确定mabmpy在氨基糖苷耐药性中的作用 有可能解释观察到的体外效率和体内功效之间的不和谐 治疗（目标2）。 MAB的极端先天抗生素耐药性为研究 多种电阻机制在该病原体中的收敛性。对这些的深入了解 各种机制对于开发用于治疗的新治疗方法至关重要 mAb感染。