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).
Multidrug resistant bacterial infections are a major global problem and new antibiotics are desperately needed. We are proposing research to enable the development of novel antibiotics based on the potent natural product moenomycin A, which inhibits bacterial cell wall biosynthesis. If successful, this project will facilitate access to a numerous analogs of moenomycin A, a key to its translation into a drug.
|Lopatniuk, M; Ostash, B; Makitrynskyy, R et al. (2015) Testing the utility of site-specific recombinases for manipulations of genome of moenomycin producer Streptomyces ghanaensis ATCC14672. J Appl Genet 56:547-50|
|Lopatniuk, M; Ostash, B; Luzhetskyy, A et al. (2014) Generation and study of the strains of streptomycetes - heterologous hosts for production of moenomycin. Russ J Genet 50:360-365|
|Mutenko, H; Makitrinskyy, R; Tsypik, O et al. (2014) Genes for biosynthesis of butenolide-like signalling molecules in Streptomyces ghanaensis, their role in moenomycin production. Russ J Genet 50:563-568|
|Makitrynskyy, Roman; Ostash, Bohdan; Tsypik, Olga et al. (2013) Pleiotropic regulatory genes bldA, adpA and absB are implicated in production of phosphoglycolipid antibiotic moenomycin. Open Biol 3:130121|
|Ostash, Bohdan; Campbell, Jennifer; Luzhetskyy, Andriy et al. (2013) MoeH5: a natural glycorandomizer from the moenomycin biosynthetic pathway. Mol Microbiol 90:1324-38|