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 细菌进化中的一个共同主题是抗生素耐药性的获取如何迅速改变 主要人类病原体的流行病学景观。碳青霉苯丙基肺炎肺炎（CRKP）， 1996年首次记录在1996年，现在在纽约市（NYC）医院流行，并在全球范围内报道。 CRKP 感染通常导致治疗指数不良；因此，遏制CRKP感染的发生率现在是 国家优先。目前，三个重叠的CRKP流行病与三个不同类别的碳纤维酶 在不同的大陆传播。加速这些流行病是碳酸碳酸酶基因的能力， 在共轭质粒上具有散布在肠杆菌科家族中。一个批判性，很差 CRKP流行的知识是质粒介导的转移和克隆的相对贡献 传播驱动区域和全球流行病学。以前，我们使用了整个基因组测序 （WGS）剖析美国主要流行CRKP序列类型的分子流行病学和进化 （ST）258。在我们的纽约医院网络中询问菌株和抗药性，我们 发现大多数ST258 CRKP菌株含有三种携带特定质粒的质粒之一 碳青霉酶类别，kpc。这些数据表明CRKP的传播可能是 质粒介导的基因转移和随后的克隆扩散。因此，我们假设这种流行是 主要是由于抗抗性的传播构成了特定宿主遗传的属性 背景。在AIM 1中，我们将纽约市网络扩展到包括一个大型美国财团，并检查 美国CRKP菌株和质粒的基因组流行病学。 AIM 2建立在见解的基础上 我们以前的研究在我们以前开发的技术中开发了通过大型CRKP的全球流行病学询问的技术 来自62个国家 /地区的临床分离株收集，目的是建造菌株的植物地理图， 质粒和碳青霉酶基因。在此目标中，我们还将直接测试CRKP应变质量的基础 通过比较传播效率研究的关联研究 质粒成各种应变背景。使用AIMS 1和2中获得的强大CRKP基因组数据，我们将 开发快速的分子检测测定法，以识别和跟踪临床环境中的CRKP菌株和质粒。 AIM 3将表征有助于高级碳青霉烯酶耐药性的非核桃烯酶因子 CRKP分离株，例如外膜外蛋白的突变，从而导致临床结局非常差。 基于此特征，将选择其中一些高度碳青霉酶抗性菌株以构建 一个新的，精心策划的菌株，用于测试新型抗生素剂。综上所述，我们的创新性 有可能在CRKP流行病学领域产生重大影响，批判性发展的方法 需要诊断平台，并探索新型抗生素对这些生物的功效。

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