The molecular basis of the epidemic blaKPC gene Klebsiella

克雷伯氏菌流行性blaKPC基因的分子基础

基本信息

批准号：
8434219
负责人：
BARRY Neal KREISWIRTH
金额：
$ 7.63万
依托单位：
UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-03-15 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8434219
关键词：
Aminoglycosides Antibiotic Resistance Antimicrobial Resistance Apoptosis Area Bacteria Biological Assay Blood Carbapenems Cells Characteristics Chromosomes Complex Cross-Sectional Studies Cytolysis DNA Transposable Elements Data Development Diagnostic Dissection Elements Enterobacteriaceae Environment Epidemic Epidemiologic Studies Escherichia coli Event Exhibits Family Fluoroquinolones Future Genes Genetic Genetic Polymorphism Genetic Variation Genomics Genotype Goals Hospitals Human Incidence Infection Infection Control Klebsiella Klebsiella pneumonia bacterium Lactams Lateral Minisatellite Repeats Modeling Molecular Molecular Epidemiology Molecular Genetics Morbidity - disease rate Multi-Drug Resistance Nature New Jersey New York New York City North America Organism Outcome Parents Pattern Phagocytosis Physical Chromosome Mapping Plasmids Play Pneumonia Public Health Relative (related person)Reporting Resistance Role San Francisco Serotyping Site Stream Treatment outcome United States Urinary tract Virulence base carbapenem resistance carbapenemase comparative experience genome sequencing killings member metropolitan mortality neutrophil novel pathogen programs public health relevance resistant strain response tertiary care trait transmission process

项目摘要

DESCRIPTION (provided by applicant): Recent reports indicating a rise in infections caused by carbapenem- resistant Klebsiella pneumoniae (KPC) in the United States, specifically the New York metropolitan area, and elsewhere have alerted clinicians, infection control teams and public health officials. KPCs typically exhibit a wide spectrum of antimicrobial resistance, and pan-resistance in some cases, thereby severely impacting treatment options and outcomes. A troubling aspect is that the resistance determinant, blaKPC is on a transposon that is harbored on transmissible plasmids. These resistance bearing plasmids have transmitted to other bacterial genera, such as E. coli. Therefore, it is critical to understand the nature and the genetic basis of spread and the acquisition of these resistance-determining elements. The goal of the present proposal is to determine the role of strains, plasmids, and transposons in the spread and emergence of blaKPC among KPC and other genera. These studies will be done in the New York area, the current epicenter of KPC strains in the US and globally. We will characterize the nature and extent of the KPC epidemic in two consecutive cross-sectional studies (years 1 and 4) to examine the molecular epidemiology of infecting isolates over the 5-year project period, including other emerging carbapenem-resistant Enterobacteriaceae. These studies will involve extensive molecular characterization of the isolates, physical and genetic mapping of resistance bearing mobile elements and determinants, including evaluating carbapenemase activity, and determining the relative virulence of circulating strains in a neutrophil model of infection. To determine whether predominant KPC clones or blaKPC-harboring plasmids have unique genomic content or organization we will conduct de novo whole genome sequencing (WGS) of major KPC strains and their plasmids. In addition, in order to examine the evolutionary trajectories (expansion and diversification) of the current epidemic clones we will perform high- throughput comparative WGS of major KPC strains using clone-specific reference strains. The information gained from the molecular epidemiologic studies on KPC strains and carbapenem-resistant Enterobacteriaceae, blaKPC -harboring plasmids, transposons and other resistance determinants will help evaluate the extent to which KPC strains are attributed to primary (clonal) transmission or acquired resistance and whether any new genotypes are emerging in this high incidence region. Our neutrophil studies will determine whether host-pathogen interaction play a role in the current overrepresentation of genotypes. The results from the genomic studies may help elucidate factors that contribute to the dissemination of predominant clones of KPC that are currently fueling the epidemic. Furthermore, deep molecular dissection of major strains will indicate patterns of genetic diversification and demonstrate clonal emergence. Accomplishing these aims will deepen our understanding of a critical, public health problem by detailing the molecular and genetic characteristics of KPC isolates in the epicenter of a developing crisis; assessing the relative virulence of circulating strains; and by examining the lateral transfer of blaKPC genes to other members of Enterobacteriaceae, events that would significantly hinder treatment and infection control programs. These data can inform current and future control strategies and in the development of rapid diagnostics.

描述（由申请人提供）：最近的报告表明，在美国，特别是纽约大都市区和其他地方，耐碳青霉烯类肺炎克雷伯菌（KPC）引起的感染有所增加，这引起了临床医生、感染控制团队和公共卫生官员的警惕。 KPC 通常表现出广泛的抗菌谱耐药性，在某些情况下甚至表现出泛耐药性，从而严重影响治疗选择和结果。一个令人不安的方面是，抗性决定簇 blaKPC 位于可传播质粒上的转座子上。这些带有抗性的质粒已经传播到其他细菌属，例如大肠杆菌。因此，了解传播的本质和遗传基础以及这些耐药决定因素的获得至关重要。本提案的目标是确定菌株、质粒和转座子在 blaKPC 在 KPC 和其他属中的传播和出现中的作用。这些研究将在纽约地区进行，纽约地区是目前美国和全球 KPC 菌株的震中。我们将在两个连续的横断面研究（第 1 年和第 4 年）中描述 KPC 流行病的性质和程度，以检查 5 年项目期间感染分离株的分子流行病学，包括其他新出现的碳青霉烯类耐药肠杆菌科细菌。这些研究将涉及分离株的广泛分子特征、耐药性移动元件和决定因素的物理和遗传图谱，包括评估碳青霉烯酶活性，并确定中性粒细胞感染模型中循环菌株的相对毒力。为了确定主要 KPC 克隆或携带 blaKPC 的质粒是否具有独特的基因组内容或组织，我们将对主要 KPC 菌株及其质粒进行从头全基因组测序 (WGS)。此外，为了检查当前流行克隆的进化轨迹（扩展和多样化），我们将使用克隆特异性参考菌株对主要 KPC 菌株进行高通量比较全基因组测序。从 KPC 菌株和耐碳青霉烯类肠杆菌科细菌、携带 blaKPC 的质粒、转座子和其他耐药决定因素的分子流行病学研究中获得的信息将有助于评估 KPC 菌株归因于原发性（克隆）传播或获得性耐药性的程度以及是否存在任何耐药性。新的基因型正在这个高发地区出现。我们的中性粒细胞研究将确定宿主与病原体的相互作用是否在当前基因型的过度表达中发挥作用。基因组研究的结果可能有助于阐明导致目前加剧流行病的 KPC 主要克隆传播的因素。此外，对主要菌株的深入分子解剖将表明遗传多样化的模式并证明克隆的出现。实现这些目标将通过详细了解正在发展的危机中心的 KPC 分离株的分子和遗传特征，加深我们对关键公共卫生问题的理解；评估流行菌株的相对毒力；并通过检查 blaKPC 基因向肠杆菌科其他成员的横向转移，这些事件将严重阻碍治疗和感染控制计划。这些数据可以为当前和未来的控制策略以及快速诊断的开发提供信息。