Antimicrobial activity of Escherichia coli Nissle 1917 microcin M

大肠杆菌 Nissle 1917 microcin M 的抗菌活性

基本信息

批准号：
10212238
负责人：
ELIZABETH M NOLAN
金额：
$ 19.38万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-07 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10212238
关键词：
Address Affect Anaerobic Bacteria Anti-Bacterial Agents Antibiotics Bacteria Catechols Cells Chelating Agents Development Diarrhea Economic Burden Elements Enterobacteriaceae Enterobactin Environment Equus caballus Escherichia coli Family Focal Infection Future Gastrointestinal tract structure Gram-Negative Bacteria Growth Health Human Immune response In Vitro Infection Intervention Iron Lead Libraries Light Link Mediating Membrane Metals Microbe Morbidity - disease rate Multi-Drug Resistance Nutrient Organism Palliative Care Patients Peptides Prevalence Probiotics Process Public Health Ribosomes Running Salmonella Salmonella enterica Siderophores Testing Therapeutic United States Work antimicrobial antimicrobial peptide cellular targeting enteric pathogen gut microbiome gut microbiota in vivo inflammatory disease of the intestine microbiota microcin mortality mutant non-typhoidal Salmonella novel therapeutic intervention pathobiont pathogen pathogenic bacteria screening siderophore receptors small molecule success targeted delivery transmission process uptake

项目摘要

SUMMARY Enterobacteriaceae are a family of Gram-negative bacteria that contains both commensals and pathogens relevant to human health. Among the most prominent pathogens of this family is non-typhoidal Salmonella enterica, a leading cause of infectious diarrhea worldwide. Key to this pathogen's success is its ability to elicit intestinal inflammation, a host response that creates a hostile gut environment where many commensals are depleted, but where Salmonella thrives, significantly increasing in abundance. During infection, pathogens must acquire essential metal nutrients such as iron, an element that is highly limited by the host. In preliminary studies, we found that the probiotic bacterium Escherichia coli Nissle 1917 can compete with Salmonella and other enteric pathogens in the inflamed gut by producing antibacterial peptides termed microcins. In particular, we found that Salmonella is susceptible to microcin M in iron-limited conditions and in the inflamed gut. The primary objective of this application is to elucidate the antimicrobial activity of E. coli Nissle's microcin M (MccM) in vitro and in vivo. Our central hypothesis is that conjugation to catecholate siderophores enables MccM to more selectively target bacteria that express specific siderophore receptors in the Fe-limited host environment, without affecting the gut microbiota at large. We plan to test our hypothesis and fulfill the objectives of this application by pursuing the following two Specific Aims. In Aim 1, we will determine whether siderophore conjugation and siderophore uptake machinery influences the antimicrobial activity of MccM, and we will identify putative cellular targets of MccM activity by screening mutant libraries. Investigate the mechanisms underlying the selectivity of MccM antimicrobial activity. In Aim 2, we will ascertain the antimicrobial activity of MccM against non-typhoidal Salmonella in vivo, and we will determine whether administration of purified MccM perturbs the gut microbiome.This work may lead to future development of microcins as therapeutics to limit colonization and transmission of non-typhoidal Salmonella, and possibly other enteric pathogens and pathobionts, in an environment that is otherwise favorable to their growth.

概括肠杆菌科是革兰氏阴性细菌的家族，其中含有共生和病原体与人类健康有关。该家族最突出的病原体是非肾小球沙门氏菌 Enterica，全世界感染性腹泻的主要原因。这种病原体成功的关键是它的引起能力肠道炎症，一种宿主反应，创造了许多共生的敌对肠道环境耗尽，但沙门氏菌繁殖，丰度显着增加。在感染过程中，病原体必须获取必需的金属营养素，例如铁，这是受宿主高度限制的元素。在初步研究中，我们发现益生菌大肠杆菌Nissle 1917可以与沙门氏菌和其他肠子竞争通过产生称为微蛋白的抗菌肽，病原体在发炎的肠道中。特别是，我们发现在铁限制的条件下和发炎的肠道中，沙门氏菌易受微蛋白M的影响。主要目标该应用是为了阐明大肠杆菌的微蛋白M（MCCM）在体外和IN中的抗菌活性体内。我们的中心假设是与脱基铁载体的共轭使MCCM更有选择性在Fe限制的宿主环境中表达特定的铁载体受体的靶向细菌，而不会影响肠道微生物群。我们计划通过追求来检验我们的假设并实现本申请的目标以下两个具体目标。在AIM 1中，我们将确定铁载体结合和铁载体是否是否摄取机械影响MCCM的抗菌活性，我们将确定推定的细胞靶标通过筛选突变库的MCCM活动。研究MCCM选择性的基础机制抗菌活性。在AIM 2中，我们将确定MCCM对非细类的抗菌活性沙门氏菌在体内，我们将确定纯化的MCCM的给药是否存在肠道微生物组。这项工作可能导致微蛋白作为治疗剂的未来发展，以限制定植和非细类沙门氏菌，可能是其他肠病原体和病原体的传播原本有利于其增长的环境。