Enabling Biotechnologies to Generate Novel Phosphoglycolipid Antibiotics

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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).