The molecular basis of the carbapenem resistance epidemic

碳青霉烯类耐药流行的分子基础

• 批准号: 10065482
• 负责人: BARRY Neal KREISWIRTH
• 金额: $ 66.74万
• 依托单位: HACKENSACK UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10065482
• 关键词: Address; Antibiotic Resistance; Antibiotics; Area; Automobile Driving; Biological; Boronic Acids; Carbapenems; Clinical; Collection; Country; Data; Enterobacteriaceae; Enzymes; Epidemic; Epidemiology; Europe; Evolution; Family; Far East; Gene Transfer; Genes; Genetic; Genomics; Goals; Hospitals; Incidence; Infection; Institution; Klebsiella; Klebsiella pneumoniae; Lipopolysaccharides; Maps; Mediating; Membrane Proteins; Molecular; Molecular Diagnostic Testing; Molecular Epidemiology; Molecular Evolution; Mutation; Nature; New York City; Organism; Outcome; Phenotype; Plasmids; Polysaccharides; Prevalence; Reporting; Resistance; South America; Specificity; Surveys; Techniques; Testing; Therapeutic Agents; Therapeutic Index; Treatment Failure; United States; Urban Hospitals; base; beta-Lactamase; carbapenem resistance; carbapenemase; comparative; comparative genomics; design; detection assay; diagnostic platform; genome sequencing; genomic data; genomic epidemiology; human pathogen; indexing; inhibitor/antagonist; innovation; insight; novel; novel therapeutics; prospective; resistance gene; resistance mechanism; resistant Klebsiella pneumoniae; resistant strain; trait; transmission process; whole genome

Summary A common theme in bacterial evolution is how the acquisition of antibiotic resistance can rapidly change the epidemiologic landscape of major human pathogens. Carbapenem Resistant Klebsiella pneumoniae (CRKp), first documented in 1996, is now epidemic in New York City (NYC) hospitals and is reported globally. CRKp infections often result in poor therapeutic indices; thus curbing the incidence of CRKp infections is now a national priority. Currently, three overlapping CRKp epidemics with three different classes of carbapenemases are spreading in different continents. Accelerating these epidemics is the ability of carbapenemase genes, harbored on conjugative plasmids, to spread across the Enterobacteriaceae family. A critical, poorly understood aspect of the CRKp epidemic is the relative contribution of plasmid-mediated transfer and clonal dissemination to driving the regional and global epidemiology. Previously, we used whole genome sequencing (WGS) to dissect the molecular epidemiology and evolution of the main US epidemic CRKp sequence type (ST) 258. Interrogating strains and resistance harboring plasmids within our network of NYC hospitals we found that the majority of ST258 CRKp strains harbor one of three common plasmids carrying a particular class of carbapenemase enzyme, KPC. These data suggest the spread of CRKp is likely the consequence of plasmid-mediated gene transfer and subsequent clonal spread. We therefore hypothesize that this epidemic is primarily due to transmission of resistance harboring plasmids uniquely adapted to specific host genetic backgrounds. In Aim 1, we expand our NYC network to include a large US consortium and to examine the genomic epidemiology of CRKp strains and plasmids across the US. Aim 2 builds on the insights and techniques developed in our previous studies to interrogate the global epidemiology of CRKp via a large clinical isolate collection from over 62 countries, with the goal of constructing a phylogeographic map of strains, plasmids and carbapenemase genes. In this Aim we will also directly test the basis of CRKp strain-plasmid association by comparative transmission efficiency studies of different carbapenemase gene-harboring plasmids into diverse strain backgrounds. Using robust CRKp genomic data obtained in Aims 1 and 2, we will develop a rapid molecular detection assay to identify and track CRKp strains and plasmids in clinical settings. Aim 3 will characterize non-carbapenemase factors that contribute to high-level carbapenemase resistance in CRKp isolates, such as mutations in outer membrane proteins, which result in very poor clinical outcomes. Based on this characterization, some of these highly carbapenemase resistant strains will be selected to build a new, well-curated panel of strains for testing novel antibiotic agents. Taken together, ours is an innovative approach with the potential to make a substantial impact in the field of CRKp epidemiology, develop critically needed diagnostic platforms, and explore efficacy of novel antibiotics against these organisms.

概括 细菌进化的一个共同主题是抗生素耐药性的获得如何迅速改变 主要人类病原体的流行病学状况。耐碳青霉烯类肺炎克雷伯菌 (CRKp)， 该病于 1996 年首次被记录，目前在纽约市 (NYC) 医院流行，并在全球范围内有报道。 CRKp 感染常常导致治疗指数不佳；因此，遏制 CRKp 感染的发生率现在是一个 国家优先事项。目前，三种不同类别的碳青霉烯酶导致三种重叠的 CRKp 流行病 正在不同的大陆传播。加速这些流行病的是碳青霉烯酶基因的能力， 携带接合质粒，在肠杆菌科中传播。批判性的、差劲的 CRKp 流行病的已知方面是质粒介导的转移和克隆的相对贡献 传播以推动区域和全球流行病学。之前，我们使用全基因组测序 （WGS）剖析美国主要流行CRKp序列类型的分子流行病学和演变 (ST) 258. 在我们的纽约市医院网络中询问携带质粒的菌株和耐药性 发现大多数 ST258 CRKp 菌株都含有三种常见质粒之一，这些质粒携带特定的 碳青霉烯酶类，KPC。这些数据表明 CRKp 的传播可能是以下原因的结果 质粒介导的基因转移和随后的克隆传播。因此我们推测这次疫情是 主要是由于携带独特适应特定宿主遗传的质粒的抗性传播 背景。在目标 1 中，我们扩展了我们的纽约网络，将一个大型美国财团纳入其中，并检查 美国各地 CRKp 菌株和质粒的基因组流行病学。目标 2 建立在洞察力和 我们之前的研究中开发了一些技术，通过大量的研究来探究 CRKp 的全球流行病学 来自超过 62 个国家的临床分离株收集，目的是构建菌株的系统发育地理学图， 质粒和碳青霉烯酶基因。在这个目标中，我们还将直接测试CRKp菌株质粒的基础 通过不同碳青霉烯酶基因携带的比较传输效率研究进行关联 质粒进入不同的菌株背景。使用目标 1 和 2 中获得的可靠 CRKp 基因组数据，我们将 开发一种快速分子检测方法来识别和跟踪临床环境中的 CRKp 菌株和质粒。 目标 3 将描述导致高水平碳青霉烯酶耐药性的非碳青霉烯酶因素 CRKp 分离物，例如外膜蛋白突变，会导致非常差的临床结果。 基于这一特征，将选择其中一些高度碳青霉烯酶抗性菌株来构建 一组精心设计的新菌株，用于测试新型抗生素药物。总而言之，我们的产品是一个创新的产品 有可能在 CRKp 流行病学领域产生重大影响的方法，批判性地发展 所需的诊断平台，并探索新型抗生素对这些生物体的功效。

项目成果

Genomic Epidemiology of Global Carbapenemase-Producing Enterobacter spp., 2008-2014.

• DOI: 10.3201/eid2406.171648
• 发表时间: 2018-06
• 期刊: Emerging infectious diseases
• 影响因子: 11.8
• 作者: Peirano G;Matsumura Y;Adams MD;Bradford P;Motyl M;Chen L;Kreiswirth BN;Pitout JDD
• 通讯作者: Pitout JDD

Colistin- and Carbapenem-Resistant Escherichia coli Harboring mcr-1 and blaNDM-5, Causing a Complicated Urinary Tract Infection in a Patient from the United States.

• DOI: 10.1128/mbio.01191-16
• 发表时间: 2016-08-30
• 期刊: mBio
• 影响因子: 6.4
• 作者: Mediavilla JR;Patrawalla A;Chen L;Chavda KD;Mathema B;Vinnard C;Dever LL;Kreiswirth BN
• 通讯作者: Kreiswirth BN

RpoE is a Putative Antibiotic Resistance Regulator of Salmonella enteric Serovar Typhi.

RpoE 是一种公认​​的肠伤寒沙门氏菌抗生素耐药性调节剂。

• DOI: 10.1007/s00284-015-0983-7
• 发表时间: 2016
• 期刊: Curr Microbiol
• 作者: Xie Xiaofang;Zhang Haifang;Zheng Yi;Li Aiqing;Wang Min;Zhou Huiqin;Zhu Xueming;Schneider Zachary;Chen Liang;Kreiswirth Barry N;Du Hong（杜鸿）
• 通讯作者: Du Hong（杜鸿）

Two for the price of one: emerging carbapenemases in a returning traveller to New York City.

• DOI: 10.1136/bcr-2018-225440
• 发表时间: 2018-07-18
• 期刊: BMJ case reports
• 影响因子: 0.9
• 作者: Mittal, Jaimie;Szymczak, Wendy A;Nori, Priya
• 通讯作者: Nori, Priya

Evaluation of Remel Spectra CRE Agar for Detection of Carbapenem-Resistant Bacteria from Rectal Swabs Obtained from Residents of a Long-Term-Care Facility.

对 Remel Spectra CRE 琼脂用于检测长期护理机构居民直肠拭子中的碳青霉烯类耐药细菌的评估。

• DOI: 10.1128/jcm.00789-15
• 发表时间: 2015
• 期刊: Journal of clinical microbiology
• 影响因子: 9.4
• 作者: LaBombardi,VincentJ;Urban,CarlM;Kreiswirth,BarryN;Chen,Liang;Osorio,Giuliana;Kopacz,Joanna;Labaze,Georges;Segal-Maurer,Sorana
• 通讯作者: Segal-Maurer,Sorana