Intrinsic modifiers of beta-lactam resistance in nosocomial Enterobacterales

医院内肠杆菌β-内酰胺耐药性的内在修饰因素

• 批准号: 10312120
• 负责人: Jacob Eric Lazarus
• 金额: $ 19.93万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-15 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10312120
• 关键词: Address; Affect; Affinity; Alleles; Antibiotic Resistance; Antibiotics; Antimicrobial susceptibility; Bacteria; Binding; Biochemistry; Biology; Carbapenems; Categories; Cause of Death; Cell Membrane Permeability; Cells; Cellular biology; Centers for Disease Control and Prevention (U.S.); Cephalosporin Resistance; Cephalosporins; Cessation of life; Clinical; Collection; Communicable Diseases; Critical Pathways; Data; Down-Regulation; Drug Design; Enterobacter cloacae; Eukaryotic Cell; General Hospitals; Genetic; Genetic Screening; Genomics; Goals; Gram-Negative Bacteria; Health; Hospitals; Human; Infection; K-Series Research Career Programs; Klebsiella aerogenes; Mass Spectrum Analysis; Massachusetts; Mediating; Membrane; Mentors; Modification; Molecular; Monobactams; Mutation; Organism; Pathway interactions; Patients; Peptidoglycan; Persons; Predisposition; Prokaryotic Cells; Proteins; Proteomics; Research; Research Personnel; Resistance; Resistance development; Resources; Scientist; Serratia marcescens; System; Techniques; Testing; Training; VDAC1 gene; Woman; amidase; antibiotic resistant infections; base; beta-Lactam Resistance; beta-Lactamase; beta-Lactams; carbapenem resistance; carbapenemase; career; clinical practice; clinically relevant; crosslink; design; health care settings; human pathogen; improved; in vivo; medical schools; mutant; novel; overexpression; pathogen; pathogenic bacteria; periplasm; protein function; response; transcriptomics

Project Summary / Abstract Increasing rates of antibiotic resistance in common bacterial pathogens threatens to reverse many of the gains made in human health over the past century. This proposal details a research plan designed to understand the basic biology of resistance to beta-lactam antibiotics in an important group of Gram-negative pathogens, the Enterobacterales. Aim 1 of this proposal concerns a novel, conserved protein that the candidate has discovered helps mediate beta-lactam resistance in the Enterobacterales. Through targeted experimentation and quantitative proteomics, the candidate will discover how this protein functions at the molecular level. Aim 2A takes a broader focus, seeking to characterize how many mutations are necessary to impart resistance in an important pathogen of hospitalized patients, Serratia marcescens. This is important to determine, because if this sort of resistance is difficult to acquire, it may be prudent for clinicians to use narrower, rather than broader antibiotics. Finally, in Aim 2B, the candidate strives to identify proteins and pathways necessary for a kind of intrinsic resistance that a group of Enterobacterales can utilize to become resistant to even the last-line carbapenem group of beta-lactams. This approach has the potential to identify new antibiotic targets. The candidate’s background includes training in biochemistry and eukaryotic cell biology, as well as the clinical practice of infectious diseases. This Mentored Clinical Scientist Research Career Development Award proposes additional training in genomics, proteomics, and transcriptomics necessary for an independent career investigating clinically relevant problems in the prokaryotic cell biology of antibiotic resistance. With the guidance of his co-mentors, the candidate will obtain this additional training using both formal coursework and hands-on training utilizing the best of the resources available at the Massachusetts General Hospital, Brigham and Women’s Hospital, and Harvard Medical School.

项目摘要 /摘要 普通细菌病原体中抗生素抗性的发生率提高，有可能逆转许多 在过去一个世纪中，人类健康的收益。该建议详细介绍了研究计划 旨在了解重要的 一组革兰氏阴性病原体，肠杆菌。 该提案的目标1涉及候选人发现的小说，构成蛋白质的帮助 介导肠杆菌中的β-内酰胺抗性。通过有针对性的实验和 定量蛋白质组学，候选者将发现该蛋白在分子上的作用 等级。 AIM 2A更加关注，试图表征需要多少突变才能 在住院的患者的重要病原体中赋予抗药性。这是 重要的是确定，因为如果难以获得这种抵抗，则可能是谨慎的 临床医生使用更狭窄而不是更广泛的抗生素。最后，在AIM 2B中，候选人努力 确定一组一组固有抗性所必需的蛋白质和途径 肠杆菌也可以使用抗抗碳酸盐群 β-内酰胺。这种方法有可能识别新的抗生素靶标。 候选人的背景还包括生物化学和真核细胞生物学的培训 作为传染病的临床实践。这项指导的临床科学家研究职业 开发奖提案在基因组学，蛋白质组学和转录组学方面进行额外的培训 独立职业对原核生物的临床相关问题所必需的必要 抗生素耐药性的细胞生物学。在他的联席会议的指导下，候选人将获得 同时使用正式课程和动手培训的额外培训使用最好的培训 马萨诸塞州综合医院，杨百翰和妇女医院可用的资源，以及 哈佛医学院。