Antimicrobial discovery from metabolomics of nematode pathogen interactions

描述（由申请人提供）：医学和农业对抗生素的广泛依赖导致抗生素耐药性的持续出现，引发了抗生素时代结束的幽灵。这场危机强调了确定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一个尚未开发的潜在的抗菌剂-化合物库，我们假设线虫在以高度复杂的微生物群落为特征的栖息地中用作对细菌和真菌的化学防御，包括堆肥土壤，腐烂的水果和分解的昆虫尸体。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.）领域的高度互补的专业知识，和C. elegans代谢组学和小分子信号传导（F.S.）。我们将重点关注线虫物种C的代谢组学分析。线虫和太平洋棱纹线虫，它们每一种都以细菌为食，并在其自然环境中暴露于各种各样的非致病性和致病性细菌和真菌，但它们对细菌的敏感性也表现出差异。我们最近对这些线虫的代谢组的研究已经确定了几类新的功能尚未确定的小分子，其化学结构表明与细菌的相互作用。我们建议开发线虫代谢物库，这些代谢物库富含这些线虫宿主对致病细菌和真菌（包括人类病原体铜绿假单胞菌和金黄色葡萄球菌）产生的化合物。然后，我们将筛选这些小分子代谢物库的抗微生物活性，利用已建立的病原体检测，遵循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确定活性化合物。我们预期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发挥作用的代谢物， 毒力机制我们的项目有可能确定新的抗菌化合物类别和潜在的新型抗感染机制，这可能有助于阻止抗生素耐药生物的浪潮。

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.