High-Risk Clones of Pseudomonas aeruginosa

项目摘要 医疗机构多药耐药铜绿假单胞菌感染暴发 多年来一直被普遍报道。我们现在知道，这些疫情大多是由一种 广泛分布的耐多药铜绿假单胞菌谱系的一小群人，它们被称为“高风险” 克隆“(HRCs)。HRCS是高度耐抗生素的PA血统，已在多个国家甚至 造成大量感染的大陆。它们出现在20世纪80年代和90年代，然后迅速 散播的。最具特征性的HRC是多位点序列类型(MLST)ST235、ST175和 ST111。HRC有问题有两个原因：(1)因为它们很容易在医院内和医院之间传播， 它们会导致不成比例的感染。(2)对抗生素高度耐药。事实上，它 似乎全世界大多数耐多药PA菌株都属于这几个HRC谱系。正如预期的那样，人力资源中心有 也被认为与特别糟糕的结果有关。是什么让人力资源中心如此广泛地传播并变得如此 对抗生素耐药，而绝大多数铜绿假单胞菌只培养一次，是抗生素 易受影响？为解决这一重要问题进行的实验相对较少，但 猜测集中在两种可能性上：(1)HRCs更有效地在胃肠道(GI)定植 而不是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宿主。 医院环境，能够更有效地在这个利基地区定居的铜绿假单胞菌菌株将具有 在机构内部和机构之间持续和传播到新患者方面具有相当大的优势。(2)人权委员会 具有使他们能够更有效地获得抗生素耐药性基因和等位基因的特性 常规铜绿假单胞菌菌株。HRC群体中蕴藏着一系列令人印象深刻的流动基因 编码抗生素耐药性的元素和染色体等位基因，这表明它们更容易修改 以获得外源DNA和进化突变，而不是常规菌株。我们假设人力资源中心 更能在胃肠道定植，并能更好地获得抗生素耐药性决定因素 而不是常规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)用小鼠模型来确定HRCs在胃肠道的定植是否比传统的P。 铜绿假单胞菌。(2)确定人力资源中心是否具有使其更容易成为 对抗生素有抗药性。(3)找出区别于传统菌株的基因座。完成 这些目标将提供对人力资源中心在医院环境中持续存在的机制的见解 获取多药耐药表型。这些洞察力反过来将突出治疗可以靶向的弱点。 防止HRCs传播和限制其抗生素耐药性的干预措施。这样的干预将 不仅影响一些最常见的铜绿假单胞菌感染，而且还影响那些最难 请客。

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.