ANTIBIOTIC DRUG DISCOVERY FROM MYXOBACTERIA

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 为了解决日益严重的抗生素耐药性问题，医学上有必要开发通过新机制发挥作用的新抗菌药。这项试验性提案旨在利用粘细菌作为天然产品抗生素的多产生产者。最近的基因组和生物信息学发现突显了这一点，惊人的~10%的粘细菌基因组包含次生代谢物生物合成基因簇。这项建议旨在解决抗生素药物发现的一个核心谜团，即天然产品是抗生素的主要来源，但发酵产率低和复杂的化学结构阻碍了它们的开发，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，即粘性细菌的捕食行为可以被利用来从遗传上选择优化的生产者菌株。这些研究的重点是天然产物抗生素TA，这是一种有前景的新型杂化聚酮-多肽抗生素，被证明是安全的，具有广谱的抗菌活性。研究的目的是了解参与调节ta表达和产生高产菌株的遗传网络。第二个目标是阐明抗生素TA的作用模式。该项目的长期重点是开发粘细菌的生物学，作为一种具有治疗前景的天然产品的来源。

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.