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，生命损失和医疗负担增加。这是一个全球性的问题，必须通过开发新型抗生素来解决。莫诺霉素是磷酸糖脂天然产物的一个小家族，从药物开发的角度来看，具有许多显着的特征，如良好的活性谱和独特的作用方式。莫诺霉素由于其不良的药代动力学而未在临床上使用，30多年来它一直是化学合成类似物的动力。莫诺霉素A （MmA）的全合成最近已经实现，尽管它不允许快速获得广泛的MmA类似物。我们确定了加纳链霉菌MmA的生物合成途径，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S.的平台，用于在体内探索肠霉素的多样性，重点是它们的脂质

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).