Intrinsic modifiers of beta-lactam resistance in nosocomial Enterobacterales

项目摘要/摘要 在常见细菌病原体中不断增加的抗生素耐药率有可能逆转许多 过去一个世纪在人类健康方面取得的进步。这份提案详述了一项研究计划。 旨在了解β-内酰胺类抗生素耐药的基本生物学基础 革兰氏阴性病原菌，肠杆菌属。 这项提案的目标1涉及候选人发现的一种新的、保守的蛋白质 介导肠杆菌属对β-内酰胺类抗生素的耐药性。通过针对性的实验和 定量蛋白质组学，候选人将发现这种蛋白质是如何在分子上发挥作用的 水平。Aim 2A的关注点更广，试图确定有多少突变是必要的 使住院患者的重要病原菌粘质沙雷氏菌产生耐药性。这是 重要的是要确定，因为如果这种阻力很难获得，那么对于 临床医生使用范围更窄的抗生素，而不是更广泛的抗生素。最后，在目标2B中，候选人努力 识别一种内在抗性所必需的蛋白质和途径 肠杆菌属甚至可以利用对最后一种碳青霉烯类变得耐药 β-内酰胺类药物。这种方法有可能确定新的抗生素靶点。 候选人的背景还包括生物化学和真核细胞生物学方面的培训 作为传染病的临床实践。指导临床科学家的研究生涯 发展奖建议在基因组学、蛋白质组学和转录组学方面进行额外的培训 独立研究原核生物的临床相关问题所必需的 抗生素耐药性的细胞生物学。在他的导师的指导下，候选人将获得 此附加培训使用正式课程和实践培训，充分利用 马萨诸塞州总医院、布里格姆和妇女医院提供的资源，以及 哈佛医学院。

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.