High-Risk Clones of Pseudomonas aeruginosa

铜绿假单胞菌的高风险克隆

基本信息

批准号：
10408175
负责人：
ALAN R HAUSER
金额：
$ 19.58万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-20 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10408175
关键词：
Address Affect Alleles Antibiotic Resistance Antibiotics Centers for Disease Control and Prevention (U.S.)Collection Country DNA Disease Outbreaks Environment Epidemic Epidemiology Gastrointestinal tract structure Genotype Geographic Locations Hospitals Infection Infection Control Practitioners Institution Intervention Knowledge Link Medical Methods Mobile Genetic Elements Modernization Molecular Multi-Drug Resistance Mutation Nosocomial Infections Outcome Patients Phenotype Population Property Pseudomonas aeruginosa Pseudomonas aeruginosa infection Reporting Structure Testing Therapeutic Intervention antibiotic resistant infections burden of illness experimental study genome sequencing genomic locus gut colonization high risk high risk population insight mouse model multidrug-resistant Pseudomonas aeruginosa novel therapeutics pathogenic bacteria prevent priority pathogen resistance allele resistance gene targeted treatment whole genome

Address Affect Alleles Antibiotic Resistance Antibiotics Centers for Disease Control and Prevention (U.S.)Collection Country DNA Disease Outbreaks Environment Epidemic Epidemiology Gastrointestinal tract structure Genotype Geographic Locations Hospitals Infection Infection Control Practitioners Institution Intervention Knowledge Link Medical Methods Mobile Genetic Elements Modernization Molecular Multi-Drug Resistance Mutation Nosocomial Infections Outcome Patients Phenotype Population Property Pseudomonas aeruginosa Pseudomonas aeruginosa infection Reporting Structure Testing Therapeutic Intervention antibiotic resistant infections burden of illness experimental study genome sequencing genomic locus gut colonization high risk high risk population insight mouse model multidrug-resistant Pseudomonas aeruginosa novel therapeutics pathogenic bacteria prevent priority pathogen resistance allele resistance gene targeted treatment whole genome

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项目摘要

Project Summary Outbreaks of multidrug-resistant (MDR) Pseudomonas aeruginosa infections within medical institutions have been commonly reported for many years. We now know that most of these outbreaks are caused by a small group of widely dispersed MDR P. aeruginosa lineages, which are have been referred to as “high-risk clones” (HRCs). HRCs are highly antibiotic resistant PA lineages that have spread across countries and even continents to cause large numbers of infections. They emerged in the 1980s and 1990s and then rapidly disseminated. The best characterized HRCs are the multilocus sequence types (MLSTs) ST235, ST175, and ST111. HRCs are problematic for two reasons: (1) Because they readily spread within and between hospitals, they cause a disproportionate number of infections. (2) They are highly resistant to antibiotics. In fact, it appears that most MDR PA strains worldwide belong to these few HRC lineages. As expected, HRCs have also been linked to particularly poor outcomes. What has allowed HRCs to spread so widely and to become so resistant to antibiotics while the vast majority of P. aeruginosa STs are cultured only once and are antibiotic susceptible? Relatively few experiments have been performed to address this important question, but speculation has focused on two possibilities: (1) HRCs more effectively colonize the gastrointestinal (GI) tract than other P. aeruginosa strains. The GI tracts of patients are a major reservoir for P. aeruginosa in the hospital setting, and strains of P. aeruginosa capable of more effectively colonizing this niche would have a considerable advantage in persisting and spreading to new patients within and between institutions. (2) HRCs have properties that allow them to more efficiently acquire antibiotic resistance genes and alleles than conventional P. aeruginosa strains. Populations of HRCs harbor an impressive array of mobile genetic elements and chromosomal alleles that encode antibiotic resistance, suggesting that they are more amendable to acquiring exogenous DNA and evolving mutations than conventional strains. We hypothesize that HRCs are better able to colonize the GI tract and better able to acquire antibiotic-resistance determinants than conventional P. aeruginosa strains. To test these hypotheses, we will perform the following Specific Aims: (1) Use a mouse model to determine whether HRCs colonize the GI tract better than conventional P. aeruginosa strains. (2) Determine whether HRCs have properties that allow them to more readily become resistant to antibiotics. (3) Identify genetic loci that distinguish HRCs from conventional strains. Completion of these aims will provide insights into the mechanisms by which HRCs persist in the hospital environment and acquire MDR phenotypes. These insights in turn will highlight vulnerabilities that can be targeted by therapeutic interventions that prevent the spread and limit the antibiotic resistance of HRCs. Such interventions would impact not only some of the most common P. aeruginosa infections but also those that are the most difficult to treat.

项目摘要医疗机构中抗多药（MDR）铜绿假单胞菌感染的爆发通常报告了很多年。我们现在知道，大多数这些爆发都是由一小部分广泛分散的MDR P.铜绿谱系，被称为“高风险克隆”（HRCS）。HRC是高度抗生素的PA谱系，它们已经遍布各个国家，甚至大陆引起大量感染。它们在1980年代和1990年代出现，然后迅速传播。最佳特征的HRC是多焦点序列类型（MLSTS）ST235，ST175和 ST111。 HRC的问题是有两个原因的：（1）因为它们很容易在医院内部和医院之间传播，所以它们会导致不成比例的感染。（2）它们对抗生素具有高度抗性。实际上，它看来全世界大多数MDR PA菌株都属于这几个HRC谱系。不出所料，HRC有也与差的结果特别差异有关。是什么使HRC如此广泛地传播并变得如此对抗生素的耐药性，而绝大多数铜绿假单胞菌ST仅培养一次，并且是抗生素易受影响的？进行了相对较少的实验来解决这个重要问题，但是猜测重点是两种可能性：（1）HRCS更有效地定居于胃肠道（GI）。比其他铜绿假单胞菌菌株。患者的胃肠道是铜绿假单胞菌的主要库医院的环境和铜绿假单胞菌的菌株能够更有效地定居此生态位在机构内部和机构之间的新患者持续和传播方面有很大的优势。（2）HRCS 具有使它们能够更有效地获得抗生素抗性基因和等位基因的特性常规的铜绿假单胞菌菌株。 HRCS的种群藏有一系列令人印象深刻的移动遗传编码抗生素耐药性的元素和染色体等位基因，表明它们更可修正比常规菌株同意外源性DNA和不断发展的突变。我们假设HRCS 能够更好地定居胃肠道，并能够更好地获取抗生素抗性决定剂比常规的铜绿假单胞菌菌株。为了检验这些假设，我们将执行以下特定目的：（1）使用小鼠模型来确定HRCS是否比常规P更好地定居GI。铜绿菌株。（2）确定HRC是否具有使它们更容易成为的属性抗抗生素。（3）确定将HRC与常规菌株区分开的遗传基因座。完成这些目标将提供有关HRC在医院环境中坚持的机制的见解，获取MDR表型。这些见解反过来将突出可以通过治疗来针对的漏洞防止扩散并限制HRC的抗生素耐药性的干预措施。这样的干预措施会不仅影响一些最常见的铜绿假单胞菌感染，而且影响最难的感染对待。