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

基本信息

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
项目类别：
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

项目摘要

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）：在医院和社区环境中，多药耐药的生物越来越普遍。 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.生物恐怖主义与特工的额外威胁肯定是通过对当前可用的抗生素具有抵抗力的设计，这一点尤其急切。该项目的长期目标是通过开发新型广谱抗菌化合物的管道来满足这一需求。当今使用的大多数抗生素来自从不到1％的微生物物种获得的天然产品，可通过常规方法栽培。其余99％的尚未耕种的物种本质上代表着发现新型抗生素的微生物的多样性。在这个阶段I项目中，我们旨在获取其中一些“缺失”物种。我们将开发一种隔离生长缓慢和稀有物种的方法，到目前为止，该物种尚未进行培养和尚未探索。传统但未经证实的智慧是，这些细菌不适合使用药物发现管道，因为它们的发现率很低，而且大规模增长是有问题的。在这里，我们提供证据表明假设都不存在，实际上，生长缓慢和稀有物种可能是抗菌发现的极好资源。该项目的具体目的是：目标1：开发长期孵化方法来培养较慢的生长和稀有细胞；目标2：扩展新物种的生长和抗菌活性的筛查；目标3：研究发现活动的化学新颖性。第一阶段的数据将证明缓慢生长的分离株是否代表了可以大量分离并有效地转化为快速生长培养物的新型物种，以及这些物种是否产生潜在的新型抗生素。第一阶段的结果将在第二阶段的培养策略中为我们的培养策略提供信息，在该阶段，我们将建立一条足以从新颖的微生物多样性池中发现新型广谱抗生素的大规模药物发现管道。公共卫生相关性：细菌中抗生素耐药性增加的威胁迫切需要开发新型抗菌剂。该提案旨在开发一种新的管道，以发现从新颖的，以前未经培养的微生物中发现抗生素，以应对即将来临的公共卫生危机。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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)
影响因子：
0
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