Drug Discovery from Slow Growing and Rare Microbial Species

从生长缓慢的稀有微生物物种中发现药物

• 批准号: 8078947
• 负责人: Amy Lynn Spoering
• 金额: $ 29.96万
• 依托单位: NOVOBIOTIC PHARMACEUTICALS, LLC
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8078947
• 关键词: Acinetobacter; Actinobacteria class; Acute; Address; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Bacteria; Biological; Biological Assay; Biological Factors; Bioterrorism; Cells; Chemicals; Collection; Data; Development; Engineering; Enterobacteriaceae; Enterococcus faecium; Environment; Escherichia coli; Fermentation; Fractionation; Fresh Water; Goals; Growth; Habitats; Incubated; Individual; Klebsiella pneumonia bacterium; Lead; Masks; Mass Spectrum Analysis; Methodology; Methods; Multi-Drug Resistance; Organism; Phase; Phylogenetic Analysis; Property; Pseudomonas aeruginosa; Public Health; Resistance; Resolution; Resources; Rest; Sampling; Seawater; Small Business Innovation Research Grant; Soil; Source; Staging; Staphylococcus aureus; Testing; Time; Vancomycin resistant enterococcus; Yeasts; antimicrobial; base; combat; community setting; cytotoxicity; drug discovery; methicillin resistant Staphylococcus aureus; microbial; microorganism; novel; pathogen; preference; public health relevance; rRNA Genes; scale up

DESCRIPTION (provided by applicant): Multidrug resistant organisms are increasingly prevalent in nosocomial and community settings. Novel antibiotics with new mechanisms of action are needed to combat the impending public health crisis of antibiotic-resistant pathogens like Staphylococcus aureus, Enterococcus faecium, Enterobacteriaceae, Pseudomonas aeruginosa, Acinetobacter baumanii, and Klebsiella pneumoniae, among others. The added threat of bioterrorism with an agent most certainly engineered to be resistant to currently available antibiotics makes this need particularly acute. The long-term goal of this project is to address this need by developing a pipeline of novel broad spectrum antimicrobial compounds. Most antibiotics in use today have come from natural products obtained from less than 1% of microbial species cultivable by conventional methods. The remaining 99% of as yet uncultivated species represent essentially an unlimited diversity of microorganisms to discover novel antibiotics. In this Phase I project we aim to access some of these "missing" species. We will develop a method to isolate slow growing and rare species that until now remained uncultivated and unexplored. It has been conventional but unproven wisdom that these bacteria are unsuited for a drug discovery pipeline because the rate of their discovery is low, and large scale growth is problematic. Here we present evidence that neither assumption holds, and that in fact, slow growing and rare species can be an excellent resource of antimicrobial discovery. The specific aims for this project are: Aim 1: Develop long-term incubation method to cultivate slower growing and rare cells; Aim 2: Scale up growth of novel species and screen for antimicrobial activity; Aim 3: Investigate the chemical novelty of the discovered activities. The data in Phase I will demonstrate whether slow growing isolates represent novel species that can be isolated in large numbers and efficiently converted into fast growing cultures and whether these species produce potentially novel antibiotics. The results in Phase I will will inform our cultivation strategy in Phase II, in which we will establish a large-scale drug discovery pipeline sufficient for discovery of novel broad-spectrum antibiotics from a novel pool of microbial diversity. PUBLIC HEALTH RELEVANCE: The threat of increased antibiotic resistance in bacteria urgently requires development of novel antimicrobials. This proposal aims to develop a new pipeline for discovery of antibiotics from novel, previously uncultivated microorganisms to combat this impending public health crisis.

描述(由申请人提供)：多重耐药生物在医院和社区环境中日益普遍。需要具有新作用机制的新抗生素来对抗迫在眉睫的公共卫生危机，这些公共卫生危机包括金黄色葡萄球菌、屎肠球菌、肠杆菌科细菌、铜绿假单胞菌、鲍曼不动杆菌和肺炎克雷伯菌等。生物恐怖主义的额外威胁，加上一种几乎肯定是经过设计的对当前可用的抗生素具有抗药性的制剂，使这一需求变得尤为迫切。该项目的长期目标是通过开发新型广谱抗菌化合物的流水线来满足这一需求。今天使用的大多数抗生素来自天然产品，从不到1%的可通过传统方法培养的微生物物种中获得。剩下的99%的尚未培育的物种基本上代表了发现新抗生素的微生物的无限多样性。在这个第一阶段的项目中，我们的目标是接触到这些“失踪”物种中的一些。我们将开发一种方法来分离生长缓慢和稀有的物种，这些物种到目前为止还没有被培养和探索。传统但未经证实的观点是，这些细菌不适合药物发现管道，因为它们的发现速度很低，而且大规模生长是有问题的。在这里，我们提出的证据表明，这两种假设都不成立，事实上，生长缓慢的稀有物种可以成为发现抗菌药物的极好资源。该项目的具体目标是：目标1：开发长期培养方法，培养生长缓慢和稀有的细胞；目标2：扩大新物种的生长并筛选抗菌活性；目标3：调查已发现活性的化学新颖性。第一阶段的数据将展示生长缓慢的菌株是否代表可以大量分离并有效转化为快速生长的培养物的新物种，以及这些物种是否产生潜在的新抗生素。第一阶段的结果将为我们第二阶段的培育战略提供参考，在这一阶段，我们将建立一个大规模的药物发现管道，足以从一个新的微生物多样性池中发现新的广谱抗生素。 与公共卫生相关：细菌中抗生素耐药性增加的威胁迫切需要开发新的抗菌剂。这项提议旨在开发一种新的管道，从以前未培养的新微生物中发现抗生素，以应对这一迫在眉睫的公共卫生危机。

项目成果

Biosynthesis and Mechanism of Action of the Cell Wall Targeting Antibiotic Hypeptin.

• DOI: 10.1002/anie.202102224
• 发表时间: 2021-06-07
• 期刊: Angewandte Chemie (International ed. in English)
• 作者: Wirtz DA;Ludwig KC;Arts M;Marx CE;Krannich S;Barac P;Kehraus S;Josten M;Henrichfreise B;Müller A;König GM;Peoples AJ;Nitti A;Spoering AL;Ling LL;Lewis K;Crüsemann M;Schneider T
• 通讯作者: Schneider T