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: 10524061
• 负责人: Jacob Eric Lazarus
• 金额: $ 19.96万
• 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/10524061
• 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; 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; Hospitalization; Hospitals; Human; Infection; K-Series Research Career Programs; Klebsiella aerogenes; Learning; Mass Spectrum Analysis; Massachusetts; Mediating; Membrane; Mentors; Modification; Molecular; Mutation; Organism; Pathway interactions; Patients; Peptidoglycan; Persons; Predisposition; Prokaryotic Cells; Proteins; Proteomics; Research; Research Personnel; Resistance; Resistance development; Resources; Scientist; Serratia marcescens; Sorting; System; Techniques; Testing; Training; VDAC1 gene; Woman; amidase; antibiotic resistant infections; beta-Lactam Resistance; beta-Lactamase; beta-Lactams; carbapenem resistance; carbapenemase; career; clinical practice; clinically relevant; crosslink; derepression; 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.

项目概要/摘要 常见细菌病原体中抗生素耐药性的增加可能会扭转许多 该提案详细介绍了一项研究计划。 旨在以重要的方式了解β-内酰胺抗生素耐药性的基本生物学 革兰氏阴性病原体，肠杆菌目。 该提案的目标 1 涉及一种新颖的保守蛋白质，候选人发现该蛋白质有助于 通过有针对性的实验和介导肠杆菌中的β-内酰胺耐药性。 定量蛋白质组学，考生将发现该蛋白质如何在分子水平上发挥作用 目标 2A 关注的范围更广，试图描述有多少突变是必要的。 使住院患者的一种重要病原体粘质沙雷氏菌产生耐药性。 确定这一点很重要，因为如果很难获得这种阻力，那么谨慎的做法可能是 最后，在目标 2B 中，候选人努力使用范围更窄的抗生素。 识别一种内在抵抗力所必需的蛋白质和途径， 肠杆菌甚至可以对最后一线碳青霉烯类细菌产生耐药性 这种方法有可能确定新的抗生素靶点。 候选人的背景包括生物化学和真核细胞生物学的培训，以及 作为传染病的临床实践，这是指导临床科学家的研究生涯。 发展奖提议在基因组学、蛋白质组学和转录组学方面进行额外培训 对于研究原核生物临床相关问题的独立职业来说是必要的 在他的共同导师的指导下，候选人将获得抗生素耐药性的细胞生物学。 这种额外的培训使用正式课程和实践培训，利用最好的 马萨诸塞州总医院、布莱根妇女医院的可用资源，以及 哈佛医学院。