Intrinsic modifiers of beta-lactam resistance in nosocomial Enterobacterales

项目总结/摘要 常见细菌病原体中抗生素耐药性的增加可能会逆转许多 在过去的世纪里人类健康所取得的成就。这份提案详细说明了一项研究计划 旨在了解β-内酰胺类抗生素耐药性的基本生物学， 一组革兰氏阴性病原体，肠球菌目。 该提案的目的1涉及候选人发现的一种新的保守蛋白质， 介导肠球菌目中的β-内酰胺耐药性。通过有针对性的实验， 定量蛋白质组学，候选人将发现这种蛋白质如何在分子水平上发挥作用。 水平目标2A采取了更广泛的关注点，试图描述需要多少突变才能 在住院患者的重要病原体粘质沙雷氏菌中赋予抗性。这是 重要的是要确定，因为如果这种阻力很难获得，它可能是谨慎的， 临床医生使用更窄的抗生素，而不是更广泛的抗生素。最后，在目标2B中，候选人努力 来鉴定一种内在抗性所必需的蛋白质和途径， 肠球菌可以利用甚至对最后一线碳青霉烯类产生耐药性， β-内酰胺这种方法有可能确定新的抗生素靶标。 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的额外培训 必要的一个独立的职业生涯调查临床相关的问题，在原核 抗生素耐药性的细胞生物学在导师的指导下，候选人将获得 这种额外的培训使用正式的课程和实践培训，利用最好的 马萨诸塞州总医院、布里格姆妇女医院的可用资源，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.