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

摘要 这次CETR的目标是使用创新策略的组合来对抗耐药传染病 疾病。特别是，我们将使用代谢组学和基因组学中的尖端方法来发现铅 小分子靶向最有问题的多重耐药(MDR)革兰氏阴性细菌和 真菌病原体。这个项目，项目2(P2)，将开发和实施代谢组学管道， 还将服务于项目1和项目3。我们将整合来自多个病原体的生物测试数据 不同的耐药表型来补充我们的代谢组学数据。基本上，我们将聘用 代谢组学驱动的体外和体内识别具有靶效的新分子的管道 同时也缺乏寄主毒性特征。识别和获取将推动这一进程的化学多样性 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； 病例将特别侧重于稀有细菌属.此外，我们寻求基本问题的答案 支撑这些新战略的问题及其相对于历史发现的高成功率 接近了。为了回答这些问题并发现下一代抗菌剂，P1项目， P2和P3有三个相同的具体目标；目标1-3都集中在共生如何提供新的细菌 作为发现具有体内抗多药耐药病原体效力的新化合物的来源。对此的支持 该项目将由四个科学核心(化学、体外、体内和作用机制)提供。 该项目的成果将是具有体内抗菌功效的新型抗菌小分子先导化合物 MDR病原体与宿主安全。

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.