Enabling Biotechnologies to Generate Novel Phosphoglycolipid Antibiotics

描述（由申请人提供）：在过去十年中，对常见抗生素的耐药性上升导致乌克兰和美国的生计减少，生命损失和医疗保健负担增加。这是一个世界性的问题，必须通过开发新的抗生素来解决。默诺霉素是一个小家族的磷酸糖脂天然产物，具有许多显着的特点，从药物开发的角度来看，如良好的活性谱和独特的作用模式。由于药代动力学差，默诺霉素没有在临床上使用，这促使了30多年来类似物的化学合成。默诺霉素A（MmA）的全合成最近已经实现，虽然它不允许快速获得广泛的MmA类似物。我们已经确定了加纳链霉菌MmA的生物合成途径，并研究了MmA行动的结构细节。在此基础上，我们提出了发展S。基于加纳的默诺霉素多样性体内探索平台，重点关注其脂质 和与药代动力学问题相关的发色团部分。本研究旨在证明：i）沙门氏菌的默诺霉素生物合成途径是如何通过代谢途径来实现的;加纳菌可以被简化和重新定向，用于通过基因工程合成新的化合物; ii）如何利用工程化的默诺霉素生产者来发现新的磷酸糖脂生物合成基因（以及相应地，新的天然产物）;和iii）什么样的调节基因可以用于过量生产默诺霉素。这项研究提供了一种创新的方法，因为将首次探索设计新型moenomycins的生物途径。也必成就 主要是在利沃夫的Ivan Franko国立大学（乌克兰）与维克托Fedorenko合作，作为子项目1（P.I. Suzanne步行者）的NIH Grant 2 P01 AI 083214 -04（P.I. Michael Gilmore）。

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).