Metabolomics driven discovery of drug leads from symbiotic bacteria

该中心的目标是使用一系列创新策略来抗击抗药性传染病。在细菌中编码小分子的基因与选择性的环境压力共同进化到共生宿主，例如产生保护性小分子的途径。利用这些共同进化的关系可以帮助指导药物发现。该项目(项目1)将使用创新战略来调查共生在抗菌药物发现方面的结果。特别是，我们将使用我们开发的基于LCMS的非靶向代谢组学，将共生天然产品与利基联系起来，并推动药物发现的努力。到目前为止，这种方法是非常有效的，但考虑到我们现在面临的抗药性传染病的威胁，将需要专业知识的协同组合，以便快速确定合适的药物线索。因此，我们不仅将使用代谢组学来推动发现工作，而且还将结合跨项目的专业知识，从战略上挖掘放线菌和变形杆菌的新来源。我们将利用全基因组测序成本的下降和通过项目2在基因组学方面的最新进展来最大化我们的产量，同时利用项目3的专业知识对物种间相互作用进行高含量筛选，以刺激目标细菌的生长和生产。项目1将与核心B密切合作，开发高通量药物发现的新范例，并向核心C提供新的抗菌剂用于体内评估。核心D将提供作用反馈机制，这将通过了解主要抗菌剂如何发挥作用来进一步推动我们的努力。这些合作努力的结果将是治疗目标微生物疾病的合适候选药物。

The goal of this CETR center is to use a combination of innovative strategies to combat drug resistant infectious diseases. Genes that encode small molecules in bacteria have coevolved with selective environmental pressures to symbiotic hosts, such as pathways that produce protective small molecules. Taking advantage of these coevolved relationships can help guide drug discovery. This project (Project 1) will use innovative strategies to investigate the outcome of symbiosis on antimicrobial drug discovery. In particular, we will use LCMS-based untargeted metabolomics developed by us to link symbiotic natural products to niche and to drive efforts in drug discovery. To date, this approach has been highly effective, but considering the threat we now face due to drug resistant infectious diseases, a synergistic combination of expertise will be required in order to quickly identify suitable drug leads. Therefore, we will not only use metabolomics to drive discovery efforts but also combine the expertise across projects to strategically mine new sources of actinomycetes and Proteobacteria. We will take advantage of the decreasing cost of whole genome sequencing and recent advances in genomics via Project 2 to maximize our output, while utilizing the expertise of Project 3 for high content screening of interspecies interactions to stimulate growth and production of targeted bacteria. Project 1 will work closely with Core B to exploit a new paradigm in high throughput drug discovery as well as provide novel antimicrobials to Core C for in vivo evaluation. Core D will provide mechanism of action feedback, which will further drive our efforts by understanding how lead antimicrobials act. The outcome of these collaborative efforts will be suitable drug candidates to treat targeted microbial diseases.