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:10294368
- 负责人:
- 金额:$ 23.48万
- 依托单位:
- 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 2023-04-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAllelesAntibiotic ResistanceAntibioticsCenters for Disease Control and Prevention (U.S.)CollectionCountryDNADisease OutbreaksEnvironmentEpidemicEpidemiologyGastrointestinal tract structureGenotypeGeographic LocationsHospitalsInfectionInfection Control PractitionersInstitutionInterventionKnowledgeLinkMedicalMethodsMobile Genetic ElementsModernizationMolecularMulti-Drug ResistanceMutationNosocomial InfectionsOutcomePatientsPhenotypePopulationPropertyPseudomonas aeruginosaPseudomonas aeruginosa infectionReportingStructureTestingTherapeutic Interventionantibiotic resistant infectionsburden of illnessexperimental studygenome sequencinggenomic locusgut colonizationhigh riskhigh risk populationinsightmouse modelmultidrug-resistant Pseudomonas aeruginosanovel therapeuticspathogenic bacteriapreventpriority pathogenresistance alleleresistance genetargeted treatmentwhole genome
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
医疗机构内多重耐药铜绿假单胞菌感染暴发疫情分析
多年来一直被报道。我们现在知道,大多数疫情是由一种
广泛分布的MDR铜绿假单胞菌谱系的小群体,其被称为"高风险"
克隆”(HRC)。HRC是高度抗生素耐药的PA谱系,已遍布各国,甚至
大陆造成大量感染。它们出现在20世纪80年代和90年代,
传播。表征最好的HRC是多位点序列类型(MLST)ST 235、ST 175和ST 235。
ST 111。HRC存在问题的原因有两个:(1)因为它们很容易在医院内和医院之间传播,
它们造成了不成比例的感染。(2)它们对抗生素有很强的抵抗力。实际上
似乎全世界大多数MDR PA菌株属于这几个HRC谱系。正如预期的那样,人权委员会
也与特别差的结果有关。是什么让人权理事会如此广泛地传播,
而绝大多数铜绿假单胞菌ST仅培养一次,
易受影响?为解决这一重要问题进行的实验相对较少,但
推测集中在两种可能性:(1)HRCs更有效地定殖于胃肠道(GI)
比其他的铜绿假单胞菌菌株要多。患者的胃肠道是铜绿假单胞菌的主要储存库,
医院环境,和铜绿假单胞菌菌株能够更有效地殖民这个利基将有一个
在机构内和机构间持续存在和传播给新患者方面具有相当大的优势。(2)人权委员
这些特性使它们能够更有效地获得抗生素抗性基因和等位基因,
常规铜绿假单胞菌菌株。HRCs的群体中存在着一系列令人印象深刻的移动的遗传
基因和染色体等位基因编码抗生素耐药性,这表明它们更容易被克隆,
获得外源DNA和进化突变的能力。我们假设人权理事会
能够更好地在胃肠道定植,
比传统的铜绿假单胞菌菌株。为了验证这些假设,我们将执行以下具体操作:
目的:(1)利用小鼠模型研究HRCs在胃肠道的定植是否优于传统的P。
铜绿菌(2)确定HRC是否具有使其更容易成为
对抗生素有抵抗力(3)确定区分HRC与传统菌株的遗传位点。完成
这些目标将提供深入了解人权理事会在医院环境中持续存在的机制,
获得MDR表型。这些见解反过来将突出可以通过治疗针对的漏洞
采取干预措施,防止HRC的传播并限制其抗生素耐药性。这些干预措施将
不仅影响一些最常见的铜绿假单胞菌感染,而且影响那些最难治疗的感染。
请客
项目成果
期刊论文数量(0)
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{{ truncateString('ALAN R HAUSER', 18)}}的其他基金
Assessing SARS-CoV-2 Variant Evolution in Patients
评估患者中的 SARS-CoV-2 变异进化
- 批准号:
10426993 - 财政年份:2021
- 资助金额:
$ 23.48万 - 项目类别:
Dynamics of Pseudomonas aeruginosa During Bacteremia
菌血症期间铜绿假单胞菌的动态
- 批准号:
10222524 - 财政年份:2020
- 资助金额:
$ 23.48万 - 项目类别:
Dynamics of Pseudomonas aeruginosa During Bacteremia
菌血症期间铜绿假单胞菌的动态
- 批准号:
10042352 - 财政年份:2020
- 资助金额:
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Systems Biology Modeling of Severe Hospital-Acquired Pneumonia
严重医院获得性肺炎的系统生物学模型
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- 批准号:
10097985 - 财政年份:2018
- 资助金额:
$ 23.48万 - 项目类别:
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