Antimicrobial peptide resistance mechanisms in adherent-invasive Escherichia coli

粘附侵袭性大肠杆菌的抗菌肽耐药机制

• 批准号: RGPIN-2015-04679
• 负责人: McPhee, Joseph
• 金额: $ 2.33万
• 依托单位: Ryerson University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=659424
• 关键词: Antimicrobial; peptide; resistance; mechanisms; adherent

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. ***

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。在这个建议中，我们描述了一个研究计划，这将使我们能够了解不同菌株的主机适应粘附入侵大肠杆菌。大肠杆菌（AIEC）能够有效地定殖宿主小肠，尽管产生通常阻止细菌定殖在该部位的抗微生物蛋白。这种适应是细菌病原体进化过程中的关键步骤。在先前的工作中，我们已经从一种这样的AIEC菌株中鉴定出对这类分子提供高水平抗性的蛋白质（ArlA、ArlB和ArlC），并且我们假设对这类分子的抗性将是AIEC菌株的一般特征，因为这些菌株通常从IBD患者的小肠分离。将以三个特定目的来测试该新假设：1）确定由ArlABC蛋白介导的抗性的分子机制，2）通过利用我们收集的其他临床AIEC菌株的集合来开发筛选以评估这是否是一般现象，以及3）通过在疾病的动物模型的背景下确定这些高度抗性菌株的特定生物学应答。该计划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从事制药行业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，因为它提供了在学术界和相关行业的研究实验室内培训高素质人才的机会，这些人才有可能在公共和私营部门工作。***