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: 10461966
• 负责人: Pallavi Ghosh
• 金额: $ 47.53万
• 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/10461966
• 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; therapeutically effective; 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.

项目总结： 脓肿分枝杆菌(Mab)是一种快速生长的NTM，可引起皮肤和软组织感染。 以及慢性肺损伤患者的肺部感染。它脱颖而出，是最具抗菌力的 具有抗药性的微生物物种，使其感染非常难以治疗。一种口服液的组合 大环内酯类和氨基糖苷类药物阿米卡星是治疗单抗的一线药物。治疗是 长期和低治愈率是令人遗憾的。这些抗生素的疗效不佳是由各种原因造成的 药物诱导单抗和宿主产生内源性耐药的机制 环境。 最近我们发现，MabHflX是一种保守的核糖体相关GTP酶，它是 大环内酯-林可胺耐药(4)。Dms_hflX缺失株中缺少HflX会导致 70年代核糖体数量增加表明HflX参与核糖体解离停滞 在抗生素存在的情况下。然而，HflX介导的抗生素耐药性的详细机制，如 此外，抗生素结合的核糖体亚基被回收的机制仍不清楚。在……里面 另一项研究证明了ARE-ABCF蛋白在大环内酯/林可胺抗性中的作用。在AIM 在这项建议中，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-林可胺耐药机制。 在另一项独立研究中，发现了缺乏锌的耻垢分枝杆菌对氨基糖苷类抗生素的抗药性。 起源于核糖体冬眠，这涉及到分枝杆菌蛋白Y(MPY)的结合。我们 假设低锌宿主环境同样会导致MPY依赖的核糖体 在单抗感染期间冬眠，并对包括阿米卡星在内的氨基糖苷类药物产生抗药性。在AIM 2 在这项提议中，我们将确定MabMPY在氨基糖苷类药物耐药性中的作用 潜在地解释了观察到的体外效率和体内效率之间的不一致 治疗(目标2)。 单抗的极端先天抗药性为我们提供了一个研究 多种抗性机制在该病原菌中的汇聚。深入了解这些 不同的机制在开发新的治疗方法方面是至关重要的 MAB感染。