Discovery of natural product-based drugs from bacterial symbionts of insects

描述(申请人提供)：我们将利用下一代DNA测序的最新进展，将天然产品与产生它们的微生物的基因组联系起来，提供对它们合成的遗传基础的见解，并为它们的发现提供搜索策略。关注全球健康：天然产品可以说是治疗传染病的最佳药物，包括那些全球危害最大的疾病。因此，我们的工作有可能导致与全球健康相关的药物。该提案的标题是：从昆虫的细菌共生体中发现基于天然产品的药物。天然产物是重要的药物或药物前体，具有广泛的药学应用，包括作为最有效的抗生素。病原微生物对抗生素耐药性的广泛和快速演变使得发现治疗感染性疾病的新疗法具有迫切的重要性。尽管有这种迫切的需求，但近几十年来，小分子的发现大幅减少，新抗生素的流水线正在迅速减少。该项目的主要目标是发现具有高治疗潜力的新天然产物(目标1)，通过体外高通量筛选和小鼠模型工作(目标2)确定这些小分子作为药物先导的抗感染潜力，并通过基因组学方法深入了解这些细菌的代谢潜力，以发现次级代谢物(目标3)。在我们的工作中，我们将专注于一个巨大的、尚未开发的新天然产品来源：与昆虫相关的放线杆菌。这些细菌似乎被它们的昆虫宿主选中，因为它们能够制造具有生物活性的小分子，Currie博士(Pi)和Clardy博士(co-I)最近的工作发现了5个新的小分子，表明它们是发现天然产物的一个有希望的来源。我们的多学科团队提出的工作承诺将影响药物发现领域，产生大量具有治疗潜力的新药线索，并通过翻译影响全球范围内耐药传染病的治疗。 公共卫生相关性：不断升级的抗菌素耐药性是一项重大的生物医学挑战。我们建议发现新的天然产物，并评估它们作为药物先导治疗对美国和全球健康具有重要意义的传染病的疗效。

DESCRIPTION (provided by applicant): We will capitalize on recent advances in next-generation DNA sequencing to link natural products with the genomes of the microbes that produce them, providing insights into the genetic underpinnings of their synthesis and informing on search strategies for their discovery. Focusing on Global Health: Natural products arguably represent the best drug leads to treat infectious diseases, including those that are the most harmful worldwide. Thus, our work has the potential to lead to drugs relevant to global health. The title of the proposal is: Discovery of natural product-based drugs from bacterial symbionts of insects. Natural products serve as critical drugs or drug precursors with broad pharmaceutical application, including serving as the most effective antibiotics. The wide-spread and rapid evolution of antibiotic-resistance in pathogenic microbes makes the discovery of novel therapeutics to treat infectious diseases of urgent importance. Despite this critical need, small molecule discovery has decreased substantially in recent decades and the pipeline of new antibiotics is rapidly diminishing. The broad goals of this project are to discover novel natural products with high therapeutic potential (Aim 1), identify the anti-infective potential of these small molecules as drug leads through in vitro high throughput screening and murine model work (Aim 2), and, through genomic approaches, to gain insights into the metabolic potential of these bacteria for discovery of secondary metabolites (Aim 3). In our work, we will focus on a large and untapped source of new natural products: insect-associated Actinobacteria. These bacteria appear to be selected by their insect host for their ability to make biologically active small molecules and recent work by Drs. Currie (PI) and Clardy (co-I) has discovered 5 new small molecules, indicating that they represent a promising source for the discovery of natural products. The work proposed by our multidisciplinary team holds the promise to impact the field of drug discovery, generate numerous new drug leads with therapeutic potential and, by translation, to impact the treatment of drug-resistant infectious diseases on a global scale. PUBLIC HEALTH RELEVANCE: Escalating antimicrobial resistance is a major biomedical challenge. We propose discovering novel natural products and evaluating their efficacy as drug leads for treating infectious diseases of significance for US and Global Heath.