Antimicrobial peptide resistance mechanisms in adherent-invasive Escherichia coli

为了适应环境，细菌必须将环境信号转化为适当的反应。了解所涉及的信号和它们被纳入观察到的表型的机制，使我们能够制定干预这些关键过程的策略。在本提案中，我们描述了一项研究计划，该计划将使我们了解不同的宿主适应粘附侵入性大肠杆菌（AIEC）菌株如何能够有效地定植宿主小肠，尽管抗菌蛋白的产生通常会阻止细菌在该部位定植。这种适应是细菌病原体进化过程中的关键一步。在之前的工作中，我们已经从一种AIEC菌株中鉴定出对这类分子具有高水平抗性的蛋白质（ArlA， ArlB和ArlC），我们假设对这类分子的抗性将是AIEC菌株的普遍特征，因为这些菌株通常从IBD患者的小肠中分离出来。这一新假设将通过三个特定目标进行验证：1)确定由ArlABC蛋白介导的耐药分子机制；2)利用我们收集的其他临床AIEC菌株开发一种筛选方法，以评估这是否是一种普遍现象；3)在动物疾病模型中确定这些高耐药菌株的特定生物学反应。这个项目将与对细菌对环境压力的反应感兴趣的基础研究人员、研究细菌-宿主相互作用的研究人员以及在制药工业中研究结肠炎治疗的研究人员高度相关。这项研究还将使加拿大受益，因为它提供了在公共和私营部门、学术界和有关工业的研究实验室中培训具有工作前景的高素质人员的机会。

In order to adapt to their environment, bacteria must convert environmental signals into an appropriate response. Understanding both the signals involved and the mechanisms by which they are incorporated into an observed phenotype allows us to develop strategies to intervene in these critical processes. In this proposal, we describe a research program that will allow us to understand how diverse strains of host-adapted adherent-invasive E. coli (AIEC) are able to effectively colonize the host small intestine in spite of the production of antimicrobial proteins that generally prevent bacterial colonization at this site. This adaptation is a critical step in the evolutionary process for bacterial pathogens. In previous work, we have identified proteins (ArlA, ArlB and ArlC) from one such AIEC strain that provide high level resistance to this class of molecules, and we hypothesize that resistance to this class of molecules will be a general feature of AIEC strains, because these strains are routinely isolated from the small intestine of IBD patients. This novel hypothesis will be tested with three specific aims 1) determining the molecular mechanism of resistance mediated by the ArlABC proteins, 2) developing a screen to assess whether this is a general phenomenon by utilizing a collection of other clinical AIEC strains that we have collected, and 3) by determining the specific biological response of these highly resistant strains in the context of an animal model of disease. This program will be highly relevant to basic researchers with an interest in bacterial responses to environmental stresses, to those studying bacterial-host interactions as well as to researchers working on treatments for colitis in the pharmaceutical industry. The research will also benefit Canada by providing the opportunity to train highly qualified personnel with prospects of work in both public and private sectors, within research labs of academia and related industries.