A New Approach for Engineering Polyketides by Cytochrome P450 C-H Oxidation

细胞色素 P450 C-H 氧化工程聚酮化合物的新方法

• 批准号: 8658294
• 负责人: Robert Vincent O'Brien
• 金额: $ 1.93万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-01 至 2014-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8658294
• 关键词: 2-acetamidoethanethiol; Alcohols; Alkenes; Anabolism; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Bacteria; Biological Factors; Collaborations; Cosmids; Crude Extracts; Cytochrome P450; DNA; DNA Gyrase; Engineering; Enzymes; Escherichia coli; Evaluation; Fermentation; Gene Cluster; Genomic DNA; Goals; Gram-Positive Bacteria; Hybrids; Laboratories; Libraries; Measurement; Modification; Molecular Structure; Peptides; Phase; Procedures; Property; Pyrroles; Reporting; Series; Text; Therapeutic; Universities; Whole-Genome Shotgun Sequencing; abstracting; analog; combat; decalin; design; feeding; functional group; genome analysis; improved; in vitro activity; methicillin resistant Staphylococcus aureus; novel strategies; oxidation; reversed phase chromatography; single molecule; tool

Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. Due to the emergence of antibiotic resistant bacteria (such as methicillin-resistant Staphylococcus aureus, MRSA) there is an urgent need to develop new antibacterial agents. Kibdelomycin is a recently discovered hybrid polyketide/non- ribosomal peptide natural product isolated from Kibdelosporangium sp. MA7385 that has broad spectrum bacteriostatic activity against both Gram negative and Gram positive bacteria (including MRSA). Intriguingly, the molecular structure of this new antibiotic contains many unusual functional groups (e.g. an exocyclic olefin, a dichloropyrrole moiety, etc.) which present opportunities for modification to improve its therapeutic properties. We are undertaking an effort to produce new derivatives of kibdelomycin through semi-synthesis and eventually by precursor directed biosynthesis. In order to realize the goal of precursor directed biosynthesis of kibdelomycin, we will identify the gene cluster of kibdelomycin through analysis of the genome of Kibdelosporangium sp. MA7385. Once we have identified the gene cluster, we will heterologously express the cluster in E. coli and study the key biosynthetic transformations involved in kibdelomycin biosynthesis (for example, we will study the biosynthesis of the dichloropyrrole moiety and also determine whether unnatural pyrrole substrates can be incorporated into the natural product). Through these combined approaches our aim is to produce a small library of kibdelomycin analogs for evaluation as bacteriostatic agents.

在此处输入文本，这是您的应用程序的新摘要信息。本节必须是否 超过30行的文本。 由于抗生素耐药性细菌的出现（如 耐甲氧西林金黄色葡萄球菌（MRSA） 迫切需要开发新的抗菌药物。 Kibdelomycin是最近发现的杂合聚酮/非- 核糖体肽天然产物分离自 Kibdelosporangium sp.MA7385具有广谱性 对革兰氏阴性菌和革兰氏阴性菌的抑菌活性 阳性细菌（包括MRSA）。有趣的是， 这种新抗生素的分子结构含有许多 不寻常的官能团（例如环外烯烃、环外烯烃、环外烯烃） 二氯吡咯部分等）这就提供了机会 以改进其治疗特性。我们 正在努力生产新的衍生物， 通过半合成和最终通过 前体定向生物合成。为实现 为了实现前体定向生物合成基布地霉素的目标， 将通过以下方法鉴定Kibdelomycin的基因簇： Kibdelosporangium sp.MA7385的基因组分析一旦 我们已经确定了基因簇， 用E表示簇。大肠杆菌，并研究其关键 克布地霉素的生物合成转化 生物合成（例如，我们将研究 二氯吡咯部分，并确定是否 非天然吡咯底物可以被引入到 天然产物）。通过这些综合方法，我们的目标是 是产生一个小的克布地霉素类似物文库， 作为抑菌剂的评价。