ANTIBIOTIC DRUG DISCOVERY FROM MYXOBACTERIA

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 为了解决日益严重的抗生素耐药性问题，有一个重要的医疗需求，开发新的抗菌药物，通过新的机制工作。 这项试点计划旨在利用粘细菌作为天然产物抗生素的多产者。 最近的基因组学和生物信息学发现突出了这一点，因为令人震惊的~ 10%的粘细菌基因组包含次级代谢物生物合成基因簇。 这项提案旨在解决抗生素药物发现的一个核心谜团也就是说，天然产物是抗生素的主要来源，但它们的发展受到低发酵产率和复杂化学结构的阻碍，使合成变得困难。 为了解决这些问题，我们的第一个目标将是测试我们的假设的可行性，即可以利用粘细菌的捕食行为来遗传选择优化的生产菌株。 这些研究的重点是天然产物抗生素TA;一种有前途的新型杂合聚酮肽抗生素，显示出安全性和广谱抗菌活性。 研究的目的是了解参与调节ta表达和产生过量生产菌株的遗传网络。 第二个目标集中在阐明抗生素TA的作用模式。 该项目的长期重点是发展粘细菌的生物学，作为有治疗前景的天然产物的来源。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. To address the growing problem of antibiotic resistance there is an important medical need to develop new antibacterials that work by novel mechanisms. This pilot proposal seeks to exploit myxobacteria as prolific producers of natural product antibiotics. Recent genomic and bioinformatic findings have highlighted this point as a stunning ~10 percent of myxobacterial genomes contain secondary metabolite biosynthetic gene clusters. This proposal seeks to tackle a central enigma of antibiotic drug discoverynamely, that natural products are the leading source of antibiotics, yet their development is hindered by low fermentation yields and complex chemical structures that make synthesis difficult. To address these problems, our first goal will be to test the feasibility of our hypothesis that the predatory behavior of myxobacteria can be exploited to genetically select optimized producer strains. A focus of these studies is on the natural product antibiotic TA; a promising novel hybrid polyketide-peptide antibiotic shown to be safe and have broad-spectrum antibacterial activity. Studies are aimed at understanding the genetic network involved in regulating ta expression and generating overproducer strains. A second goal is focused on elucidating the mode of action for antibiotic TA. The long term focus of this project is to develop the biology of myxobacteria as a source of therapeutically promising natural products.