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).

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
Fogarty International Center (FIC)
Type
Small Research Grants (R03)
Project #
5R03TW009424-02
Application #
8633483
Study Section
Special Emphasis Panel (ZRG1-BDA-Q (55))
Program Officer
Sina, Barbara J
Project Start
2013-03-11
Project End
2016-02-29
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
2
Fiscal Year
2014
Total Cost
$38,831
Indirect Cost
Name
Harvard University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
Ostash, Bohdan; Campbell, Jennifer; Luzhetskyy, Andriy et al. (2013) MoeH5: a natural glycorandomizer from the moenomycin biosynthetic pathway. Mol Microbiol 90:1324-38
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