SBIR Phase I: A Natural Product Drug Discovery Platform Based on High-Throughput Elicitor Screening (HiTES)

这个小企业创新研究（SBIR）第一阶段项目的更广泛的影响/商业潜力将是开发一种新的小分子药物发现平台，该平台可以触发隐秘微生物代谢物的生产，作为有可能针对一系列疾病的新药。这项技术将解决与新药开发相关的痛点，如时间长、成本高。通过使用专有工艺和已建立的激发子分子集合，可以迫使微生物产生天然产物，提供合成分子可能无法实现的生物活性。该技术是目前唯一不需要基因和克隆的筛选平台，首先关注生物活性，实现快速高效的生物分子发现。该平台最初将用于抗生素/抗病毒药物市场，未来将应用于抗肿瘤和免疫抑制药物。这个项目有潜力通过提供源源不断的新型候选药物来解决一系列未被满足的医疗需求，从而改善美国公众的健康。这个小企业创新研究（SBIR）一期项目旨在开发一种基于高通量启动子筛选（HiTES）的新型小分子药物发现平台，这是一种快速、简单的方法，可触发微生物隐代谢产物的产生，并在不需要基因组测序、克隆或遗传学的情况下对其活性进行分析。存在大量未开发的天然产物，以“隐式”生物合成基因簇的形式编码在微生物基因组中，在实验室条件下不表达。技术目标是提高该平台的产量/吞吐量，评估和优化化学多样性，并将该平台扩展到引起公共卫生关注的新的耐抗生素病原体。多个细菌物种的沉默基因将被激活以产生隐代代谢物，目标是产生5000个诱导代谢组，这些代谢组将使用质谱法进行表征。将建立一个工作流程，将针对多种病原体的生物活性测定与海地感染病毒筛查相结合。最后，内部软件将更新，以包括新化学，所需生物活性和缺乏细胞毒性方面的优先级。第一阶段的成功完成将证明HiTES与生物活性研究和软件相结合的实施和使用能力，以识别具有前景生物活性的化学新颖和独特化合物。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

The broader impact/commercial potential of this Small Business Innovation Research (SBIR) Phase I project will be the development of a novel, small-molecule drug discovery platform that triggers the production of cryptic microbial metabolites for use as new pharmaceuticals with the potential to target a range of diseases. This technology will address pain points associated with the development of new drugs, such as long timelines and high costs. By using a proprietary process and established collection of elicitor molecules, microorganisms can be compelled to generate natural products that offer biological activities that may be impossible with synthetic molecules. The proposed technology is the only screening platform that is free of genetics and cloning, focusing on bioactivity first, and enabling rapid and efficient biomolecule discovery. Initially the platform will be used to target the antibiotic/antiviral market, with future applications for anti-tumor and immunosuppressant drugs. This project has the potential to improve the health of the American public by providing a steady stream of novel drug candidates to address a range of unmet medical needs. This Small Business Innovation Research (SBIR) Phase I project aims to develop a novel, small-molecule drug discovery platform based on High-Throughput Elicitor Screening (HiTES), a rapid, simple method for triggering production of microbial cryptic metabolites and interrogating their activities without the need for genome sequencing, cloning, or genetics. There is a large untapped store of natural products in the form of ‘cryptic’ biosynthetic gene clusters encoded in microbial genomes that are not expressed under laboratory conditions. The technical objectives are to increase output/throughput of the platform, assess and optimize chemical diversity, and expand the platform to new antibiotic-resistant pathogens of public health concern. Silent genes across multiple bacterial species will be activated to generate cryptic metabolites with the goal of producing 5,000 induced metabolomes, which will be characterized using mass spectrometry. A workflow will be created that integrates bioactivity assays against multiple pathogens with HiTES screening. Finally, in-house software will be updated to include prioritization in terms of novel chemistry, desired bioactivity, and lack of cytotoxicity. Successful Phase I completion will demonstrate the ability to implement and use HiTES multiplexed with bioactivity studies and software to identify chemically-novel and unique compounds with promising bioactivities.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.