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

• 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
• 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

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，特别是纽约大都会地区和其他地方，由碳青霉烯耐药肺炎克雷伯氏菌(KPC)引起的感染有所上升，这已经提醒了临床医生、感染控制小组和公共卫生官员。KPCS通常表现出广泛的抗菌素耐药性，在某些情况下表现为泛耐药，从而严重影响治疗选择和结果。一个令人不安的方面是，抗性决定因素blaKPC位于一个转座子上，该转座子位于可传播的质粒上。这些携带耐药性的质粒已经传播到其他细菌属，如大肠杆菌。因此，了解传播的性质和遗传基础以及这些抗性决定因素的获得至关重要。本提案的目的是确定菌株、质粒和转座子在blaKPC在KPC和其他属中传播和出现的作用。这些研究将在纽约地区进行，该地区目前是美国和全球KPC菌株的中心。我们将在连续两项横断面研究(第1年和第4年)中确定KPC疫情的性质和范围，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，携带耐药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，以及在中性粒细胞感染模型中确定流通菌株的相对毒力。为了确定主要的KPC克隆或携带KPC的质粒是否具有独特的基因组内容或结构，我们将对主要的KPC菌株及其质粒进行从头测序(WGS)。此外，为了检查当前流行克隆的进化轨迹(扩展和多样化)，我们将使用克隆特定的参考菌株对主要KPC菌株进行高通量比较WGS。从KPC菌株和耐碳青霉烯肠杆菌、blaKPC携带的质粒、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菌株在多大程度上归因于原发(克隆)传播或获得性耐药，以及在这个高发地区是否出现了新的基因型别。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目前基因类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促成目前助长疫情的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性的模式，并证明克隆的出现。实现这些目标将通过详细描述处于发展中的危机震中的KPC分离株的分子和基因特征，评估流通菌株的相对毒力，以及通过检查blaKPC基因向肠杆菌科其他成员的横向转移，加深我们对一个关键的公共卫生问题的理解，这些事件将显著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发展提供信息。