Enabling Biotechnologies to Generate Novel Phosphoglycolipid Antibiotics

描述(申请人提供)：在过去的十年里，乌克兰和美国对常见抗生素的抗药性上升，导致生计减少，生命丧失，医疗负担增加。这是一个世界性的问题，必须通过开发新类别的抗生素来应对。从药物开发的角度来看，莫诺菌素是一小类磷脂天然产物，具有许多显著的特征，如良好的活性光谱和独特的作用模式。莫诺霉素由于药代动力学不佳而没有在临床上使用，30多年来一直推动类似物的化学合成。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。我们已经确定了甘纳链霉菌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链霉菌的体内研究平台，用于研究丝裂霉素的多样性，重点放在它们的脂类上。 和发色团部分，这与药代动力学问题有关。它计划展示i)如何通过基因工程简化和重新定位莫诺霉素的生物合成途径以合成新的化合物；ii)如何利用工程化的莫诺霉素产生者来发现新的磷脂生物合成基因(以及相应的新的天然产物)；以及iii)什么样的调控基因可以被用来过量生产莫诺霉素。这项研究提供了一种创新的方法，因为将首次探索一种生物途径来设计新型的丝裂霉素。我会做到的 主要是在利沃夫国立大学(乌克兰)与维克多·费多连科合作，作为国家卫生研究院赠款2P01AI083214-04(P.I.Michael Gilmore)分项目1(P.I.Suzanne Walker)中提议的工作的延伸。

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).