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: 8610873
• 负责人: BARRY Neal KREISWIRTH
• 金额: $ 56.45万
• 依托单位: RBHS-NEW JERSEY 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 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8610873
• 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; Health; 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; 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，由甲壳虫抗碳纤维的肺炎克雷伯氏菌（KPC）引起的感染增加，尤其是纽约大都会地区，其他地方也警告了临床医生，感染控制小组和公共卫生官员。 KPC通常表现出广泛的抗菌素耐药性，在某些情况下具有泛滥，从而严重影响治疗方案和结果。一个令人不安的方面是，抗性决定因素BlakPc在转座子上，该转座子在可透透质粒上含有的转座子。这些耐药性质粒已传播到其他细菌属，例如大肠杆菌。因此，了解传播的性质和遗传基础以及对这些抵抗确定的元素的获取至关重要。本提案的目的是确定菌株，质粒和转座子在KPC和其他属中BLAKPC的传播和出现中的作用。这些研究将在纽约地区进行，美国目前在美国乃至全球的KPC菌株中心。我们将在两项连续的横截面研究（第1和4年）中表征KPC流行的性质和程度，以检查5年项目期间感染分离株的分子流行病学，包括其他新兴的碳青霉苯甲酸乙酰基肠细菌。这些研究将涉及分离株的广泛分子表征，耐药性轴承元件和决定因素的物理和遗传图，包括评估碳青霉酶活性，并确定感染中性粒细胞模型中循环菌株的相对毒力。为了确定主要的KPC克隆或blakpc-Harboring质粒是否具有独特的基因组含量或组织，我们将对主要KPC菌株及其质粒进行从头开始的整个基因组测序（WGS）。此外，为了检查当前流行病克隆的进化轨迹（扩展和多样化），我们将使用克隆特异性参考菌株对主要KPC菌株的高吞吐量比较WGS进行。从分子流行病学研究中获得的有关KPC菌株和抗碳青霉烯的肠杆菌科，BlakPC质质粒，转座子和其他耐药性决定因素将有助于评估哪些KPC菌株归因于任何新的遗产，以及任何是新的遗传菌株的范围，以及任何是新的Genotip归因于任何繁殖的gpc菌株。我们的中性粒细胞研究将确定宿主 - 病原体相互作用是否在当前基因型的过度代表性中起作用。基因组研究的结果可能有助于阐明有助于传播KPC主要克隆的因素，而KPC目前正在加剧流行病。此外，主要菌株的深层分子解剖将指示遗传多样化的模式，并表明克隆出现。实现这些目标将通过详细介绍发展危机中心中KPC分离株的分子和遗传特征来加深我们对关键的公共卫生问题的理解；评估循环菌株的相对毒力；通过检查BlakPC基因向肠杆菌科的其他成员的横向转移，这将大大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。