Identification of novel MDR antimicrobials from symbioses between terrestrial and marine invertebrates and rare microbial taxa

从陆地和海洋无脊椎动物与稀有微生物类群之间的共生中鉴定新型耐多药抗菌剂

• 批准号: 10592387
• 负责人: TIMOTHY S BUGNI
• 金额: $ 101.32万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10592387
• 关键词: Identification; novel; MDR; antimicrobials; symbioses

ABSTRACT The goal of this CETR is to use a combination of innovative strategies to combat drug resistant infectious diseases. In particular, we will use cutting edge methods in metabolomics and genomics to discover lead small molecules targeting the most problematic multi-drug resistant (MDR) Gram-negative bacterial and fungal pathogens. This project, Project 2 (P2), will develop and implement a metabolomics pipeline that will also serve Project 1 and Project 3. We will integrate bioassay data from multiple pathogens exhibiting diverse drug resistant phenotypes to supplement our metabolomics data. Essentially, we will employ metabolomics-driven pipeline to identify novel molecules with target efficacy both in vitro and in vivo againswhile also lacking host toxicity traits. To identify and access chemical diversities that will drive this project, we will target symbiotic microbes associated with i) marine invertebrates, and ii) insects; in all cases a particular focus will be placed on rare bacterial genera. Additionally, we seek answers to basic questions underpinning these new strategies and their high success rates relative to historical discovery approaches. To answer these questions and discover the next generation of antimicrobials, projects P1, P2 and P3 share three identical specific aims; Aims 1-3 all focus on how symbioses provide novel bacteria as sources for new compound discovery with in vivo efficacy against MDR pathogens. Support for this project will be supplied by four scientific cores (Chemistry, In Vitro, In Vivo, and Mechanism of Action). The outcome of this project will be novel antimicrobial small molecule leads with in vivo efficacy against MDR pathogens and host safety.

抽象的 该 CETR 的目标是利用创新策略的组合来对抗耐药性传染病 疾病。特别是，我们将使用代谢组学和基因组学的尖端方法来发现铅 针对最有问题的多重耐药 (MDR) 革兰氏阴性细菌和 真菌病原体。该项目，即项目 2 (P2)，将开发和实施一个代谢组学流程， 还将服务于项目 1 和项目 3。我们将整合多种病原体的生物测定数据 不同的耐药表型来补充我们的代谢组学数据。本质上，我们将雇用 代谢组学驱动的管道，用于识别在体外和体内具有目标功效的新型分子 同时也缺乏宿主毒性特征。识别和获取可推动这一目标的化学多样性 项目中，我们将针对与 i) 海洋无脊椎动物和 ii) 昆虫相关的共生微生物；总共 在某些情况下，将特别关注稀有细菌属。此外，我们寻求基本问题的答案 支持这些新策略的问题及其相对于历史发现的高成功率 接近。为了回答这些问题并发现下一代抗菌药物，P1 项目， P2和P3有三个相同的具体目标；目标 1-3 都集中于共生如何提供新细菌 作为发现体内具有抗 MDR 病原体功效的新化合物的来源。支持这个 该项目将由四个科学核心（化学、体外、体内和作用机制）提供。 该项目的成果将是新型抗菌小分子先导化合物，具有体内功效 MDR 病原体和宿主安全。