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）：在过去的十年中，对普通抗生素的抗药性的兴起导致生计减少，丧生丧生和乌克兰和美国的医疗保健负担增加。这是一个在全球范围内的问题，必须通过开发新的抗生素来抵消。 Moenomycins是一小部分磷脂天然产品，从药物发育的角度来看，具有许多显着特征，例如良好的活性和独特的作用方式。由于药代动力学不良，因此未在临床上使用Moenomycins，该药代动力学不良，该药代动力学已有30多年的动机化学合成类似物。最近已经实现了Moenomycin A（MMA）的总合成，尽管它不允许快速访问广泛的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，我们建议开发基于加纳的链球菌的平台，用于体内探索Moenomycins的多样性，重点是他们的脂质和发色团部分，与药代动力学问题有关。计划证明i）如何简化和重新定位加拿大链球菌的Moenomycin生物合成途径，以通过基因工程合成新化合物； ii）如何利用工程化的Moenomycin生产商发现新型的磷酸糖脂生物合成基因（以及相应的新型天然产物）； iii）哪种调节基因可用于过量产生摩纳霉素。这项研究提供了一种创新的方法，因为将首次探索一种探索新型Moenomycins的生物学途径。将完成主要是在伊万·弗兰科（Ivan Franko）国立大学（乌克兰）与维克多·费多伦科（Victor Fedorenko）合作的，这是NIH 2P01AI083214-04的Subproject 1（P.I. Suzanne Walker）提议的工作的扩展（P.I. Michael Gilmore）。