Drug Discovery from Slow Growing and Rare Microbial Species

描述（由申请人提供）：多重耐药微生物在医院和社区环境中越来越普遍。需要具有新作用机制的新型抗生素来对抗即将到来的耐药性病原体的公共卫生危机，所述耐药性病原体如金黄色葡萄球菌、屎肠球菌、肠杆菌科、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，加上一种肯定能对目前可用的抗生素产生抗药性的制剂，使这一需求特别迫切。该项目的长期目标是通过开发新型广谱抗菌化合物来满足这一需求。目前使用的大多数抗生素都来自天然产物，这些天然产物是从不到1%的可通过常规方法培养的微生物物种中获得的。剩余的99%尚未被培养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，我们的目标是接近这些“失踪”的物种。我们将开发一种方法来分离生长缓慢和稀有的物种，直到现在仍然没有栽培和探索。传统但未经证实的观点认为，这些细菌不适合药物发现管道，因为它们的发现率很低，并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，生长缓慢和稀有的物种可以是抗菌剂发现的一个很好的资源。该项目的具体目标是：目标1：开发长期孵育方法，以培养生长较慢和稀有的细胞;目标2：扩大新物种的生长并筛选抗菌活性;目标3：研究已发现活性的化学新颖性。第一阶段的数据将证明生长缓慢的分离株是否代表可以大量分离并有效转化为快速生长培养物的新菌种，以及这些菌种是否产生潜在的新型抗生素。第一阶段的结果将为我们第二阶段的培养策略提供信息，在第二阶段，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库中发现新的广谱抗生素。 公共卫生相关性：细菌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，用于从以前未培养的新型微生物中发现抗生素，以应对这一即将到来的公共卫生危机。

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.