Antimicrobial discovery from metabolomics of nematode pathogen interactions

从线虫病原体相互作用的代谢组学中发现抗菌药物

基本信息

批准号：
9120790
负责人：
Dennis H Kim
金额：
$ 62.17万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-30 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9120790
关键词：
Affect Agriculture Animals Anti-Infective Agents Antibiotic Resistance Antibiotic-resistant organism Antibiotics Bacteria Biological Assay Caenorhabditis elegans Chemical Structure Chemicals Complex Compost Dependence Development Environment Escherichia coli Exhibits Food Fractionation Fruit Gene Expression Growth Habitats Health High Pressure Liquid Chromatography Host Defense Human Infection Insecta Laboratories Lead Libraries Life Mediating Medicine Methods Microbe Microbial Biofilms Microbial Physiology Natural Immunity Nematoda Nematode infections Nucleic Acids Pathogenesis Pathogenicity Pathway interactions Predisposition Pseudomonas aeruginosa Research Proposals Resistance Sampling Serratia marcescens Signal Transduction Soil Source Staphylococcus aureus Therapeutic Agents Virulence adaptive immunity antimicrobial bacterial resistance base chemical synthesis combat comparative experience feeding fungus in vivo innovation killings metabolome metabolomics microbial microbial colonization microbiome microorganism microorganism metabolism novel novel therapeutics pathogen pathogenic bacteria protein function response reversed phase chromatography screening small molecule small molecule libraries stem

项目摘要

DESCRIPTION (provided by applicant): The widespread dependence on antibiotics in medicine and agriculture have resulted in the continued emergence of antibiotic resistance, raising the specter of the end of the antibiotic era. This crisis has underscored the need for the identification of new antibiotics and anti-infective strategies. Our research proposal focuses on the exploration of an untapped potential reservoir of antimicrobials-compounds that we hypothesize nematodes employ as chemical defense against bacteria and fungi, in habitats characterized by highly complex microbiomes, including compost soil, rotting fruit, and decomposing insect carcasses. Our proposal brings together the highly complementary expertise from the field of Caenorhabditis elegans innate immunity and host-microbe interactions (D.K.), and from the field of C. elegans metabolomics and small- molecule signaling (F.S.). We will focus on metabolomic analysis of the nematode species C. elegans and Pristionchus pacificus, each of which feed on bacteria and are exposed to a wide variety of non-pathogenic and pathogenic bacteria and fungi in their natural environments, but which also exhibit differences in susceptibility to bacteria. Our recent studies of the metabolomes of these nematodes have identified several novel classes of small molecules of yet undetermined function that have chemical structures suggestive of interactions with bacteria. We propose to develop nematode metabolite libraries that are enriched for compounds produced by these nematode hosts in response to pathogenic bacteria and fungi, including the human pathogens Pseudomonas aeruginosa and Staphylococcus aureus. We will then screen these small molecule metabolite libraries for antimicrobial activity, taking advantage of established pathogenesis assays that follow microbial proliferation and survival of the nematode host, with subsequent definitive identification of active compounds via comparative metabolomics, and chemical synthesis. We anticipate finding compounds that directly affect bacterial and fungal viability as well as metabolites that function through the modulation of microbial colonization and virulence mechanisms. Our project has the potential to identify new classes of antimicrobial compounds and potentially novel anti-infective mechanisms that may help stem the tide of antibiotic resistant organisms.

描述（申请人提供）：医药和农业对抗生素的广泛依赖导致抗生素耐药性不断出现，引发了抗生素时代终结的担忧。这场危机凸显了寻找新抗生素和抗感染策略的必要性。我们的研究计划侧重于探索未开发的潜在抗菌化合物库，我们假设线虫在以高度复杂的微生物组为特征的栖息地（包括堆肥土壤、腐烂的水果和腐烂的昆虫尸体）中利用这些化合物来对抗细菌和真菌。我们的提案汇集了来自秀丽隐杆线虫先天免疫和宿主微生物相互作用（D.K.）领域以及来自秀丽隐杆线虫代谢组学和小分子信号传导（F.S.）领域的高度互补的专业知识。我们将重点关注线虫种线虫 C. elegans 和 Pristionchus pacificus 的代谢组学分析，这两种线虫均以细菌为食，并在自然环境中接触多种非病原性和病原性细菌和真菌，但它们在对细菌的敏感性。我们最近对这些线虫代谢组的研究发现了几类新的小分子，其功能尚未确定，它们的化学结构表明与细菌有相互作用。我们建议开发线虫代谢库，该库富含这些线虫宿主响应病原细菌和真菌（包括人类病原体铜绿假单胞菌和金黄色葡萄球菌）而产生的化合物。然后，我们将筛选这些小分子代谢文库的抗菌活性，利用已建立的发病机制测定，跟踪微生物增殖和线虫宿主的存活，随后通过比较代谢组学和化学合成明确鉴定活性化合物。我们预计会发现直接影响细菌和真菌活力的化合物以及通过调节微生物定植和功能发挥作用的代谢物。毒力机制。我们的项目有潜力识别新型抗菌化合物和潜在的新型抗感染机制，这可能有助于阻止抗生素耐药性生物体的出现。