Enabling Biotechnologies to Generate Novel Phosphoglycolipid Antibiotics

利用生物技术生产新型磷酸糖脂抗生素

基本信息

批准号：
8411474
负责人：
Suzanne Walker
金额：
$ 5.69万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-03-11 至 2016-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8411474
关键词：
Address Affinity Anabolism Animal Model Animal Nutrition Antibiotic Resistance Antibiotics Bacterial Infections Bambermycins Bioavailable Biological Biological Factors Biological Testing Biotechnology Carbohydrates Cell Wall Chemicals Clinical Collaborations Complex Development Drug Kinetics Elements Engineering Enzymes Family Fermentation Genes Genetic Genetic Engineering Grant Half-Life Healthcare Improve Access Infection Knowledge Lead Length Lipids Metabolism Methods Modification Multi-Drug Resistance Mutagenesis Parents Pathway interactions Peptidoglycan glycosyltransferase Pharmaceutical Preparations Production Property Regulation Regulator Genes Research Resistance Route Source Specificity Streptomyces Techniques Teichoic Acids Time Translations Ukraine United States National Institutes of Health Universities Vancomycin resistant enterococcus Walkers Work analog antimicrobial base carboxyl group chemical synthesis chromophore combat drug development gene function in vivo inhibitor/antagonist innovation methicillin resistant Staphylococcus aureus moenomycin A mutant novel overexpression parent grant pharmacophore prevent programs public health relevance research study scaffold tool

项目摘要

DESCRIPTION (provided by applicant): The rise of resistance to common antibiotics over the last decade has resulted in reduced livelihood, lost lives and an increased healthcare burden both in Ukraine and USA. This is a worldwide problem, which has to be countered via the development of new classes of antibiotics. Moenomycins are a small family of phosphoglycolipid natural products that possess a number of remarkable features from the drug development point of view, such as a good spectrum of activity and a unique mode of action. Moenomycins are not used clinically because of poor pharmacokinetics, which for more than 30 years motivated chemical synthesis of analogs. Total synthesis of moenomycin A (MmA) has recently been realized, although it does not allow for a rapid access to a wide range of MmA analogs. We have identified the Streptomyces ghanaensis MmA biosynthetic pathway and studied structural details of MmA action. Based on this knowledge, we propose to develop the S. ghanaensis-based platform for in vivo exploration of the diversity of moenomycins, with a focus on their lipid and chromophore portions, which are relevant to the pharmacokinetic issues. It is planned to demonstrate i) how the moenomycin biosynthetic pathway of S. ghanaensis can be simplified and reoriented for the synthesis of new compounds via genetic engineering; ii) how engineered moenomycin producers can be exploited to discover novel phosphoglycolipid biosynthetic genes (and, correspondingly, novel natural products); and iii) what kind of regulatory genes can be used to overproduce moenomycins. This research provides an innovative approach since a biological route to engineer novel moenomycins will be explored for the first time. It will be done primarily at Ivan Franko National University of Lviv (Ukraine) in collaboration with Victor Fedorenko, as an extension of work proposed in Subproject 1 (P.I. Suzanne Walker) of NIH Grant 2P01AI083214-04 (P.I. Michael Gilmore).

描述（由申请人提供）：过去十年中，常见抗生素耐药性的上升导致乌克兰和美国的生计减少、生命损失和医疗负担增加。这是一个世界性问题，必须通过开发新型抗生素来解决。默诺霉素是一小类磷酸糖脂天然产物，从药物开发的角度来看，它具有许多显着的特征，例如良好的活性谱和独特的作用方式。由于药代动力学较差，默诺霉素并未在临床上使用，30 多年来，这种药代动力学一直推动着类似物的化学合成。最近已经实现了默诺霉素 A (MmA) 的全合成，尽管它无法快速获得多种 MmA 类似物。我们已经确定了加纳链霉菌 MmA 生物合成途径并研究了 MmA 作用的结构细节。基于这些知识，我们建议开发基于 S. ghanaensis 的平台，用于体内探索默诺霉素的多样性，重点是其脂质和发色团部分，与药代动力学问题相关。计划展示 i) 如何简化和重新调整加纳沙门氏菌的默诺霉素生物合成途径，以通过基因工程合成新化合物； ii) 如何利用工程改造的默诺霉素生产者来发现新型磷酸糖脂生物合成基因（以及相应的新型天然产物）； iii) 什么样的调控基因可用于过量生产默诺霉素。这项研究提供了一种创新方法，因为将首次探索设计新型莫诺霉素的生物途径。将会完成主要在利沃夫伊万·弗兰科国立大学（乌克兰）与 Victor Fedorenko 合作，作为 NIH 拨款 2P01AI083214-04（P.I. Michael Gilmore）的子项目 1（P.I. Suzanne Walker）中提议的工作的延伸。