ANTIBIOTIC DRUG DISCOVERY FROM MYXOBACTERIA

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 为了解决日益严重的抗生素耐药性问题，迫切需要开发通过新机制发挥作用的新型抗菌药物。 该试点提案旨在利用粘细菌作为天然产物抗生素的多产生产者。 最近的基因组和生物信息学研究结果强调了这一点，因为令人震惊的是，大约 10% 的粘细菌基因组含有次级代谢物生物合成基因簇。 该提案旨在解决抗生素药物发现的一个核心谜团，即天然产物是抗生素的主要来源，但发酵产量低和化学结构复杂导致合成困难，阻碍了其发展。 为了解决这些问题，我们的首要目标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从基因上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；一种有前景的新型杂合聚酮肽抗生素，被证明是安全的并且具有广谱抗菌活性。 研究旨在了解参与调节 ta 表达和产生过度生产菌株的遗传网络。 第二个目标是阐明抗生素 TA 的作用方式。 该项目的长期重点是开发粘细菌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.