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型的小分子药物发现平台，该平台可以触发神秘微生物代谢产物的生产，用作具有针对一系列疾病潜力的新药。这项技术将解决与新药开发相关的痛点，例如时间长和成本高。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，这些天然产物提供合成分子可能不可能的生物活性。这项技术是唯一一个不受遗传学和克隆限制的筛选平台，首先关注生物活性，并能够快速有效地发现生物分子。最初，该平台将用于针对抗生素/抗病毒药物市场，未来将用于抗肿瘤和免疫抑制药物。该项目有可能通过提供源源不断的新型候选药物来解决一系列未满足的医疗需求，从而改善美国公众的健康。这个小企业创新研究（SBIR）第一阶段项目旨在开发一种基于高通量激发子筛选（HiTES）的新型小分子药物发现平台，这是一种快速，简单的方法，用于触发微生物隐蔽代谢产物的产生并询问其活性，而无需基因组测序，克隆或遗传学。有大量未开发的天然产物储存在微生物基因组中编码的“神秘”生物合成基因簇的形式中，这些基因簇在实验室条件下不表达。技术目标是增加平台的产出/吞吐量，评估和优化化学多样性，并将平台扩展到新的具有抗药性的公共卫生病原体。跨多个细菌物种的沉默基因将被激活以产生隐藏的代谢物，目标是产生5，000个诱导代谢物组，其将使用质谱法进行表征。将创建一个工作流程，将针对多种病原体的生物活性测定与HiTES筛选相结合。最后，将更新内部软件，以包括新化学、所需生物活性和无细胞毒性方面的优先级。第一阶段的成功完成将证明实施和使用HiTES与生物活性研究和软件复用的能力，以识别具有有前途的生物活性的化学新颖和独特的化合物。该奖项反映了NSF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.