Challenges and Hallmarks of Establishing Alkylacetylphosphonates as Probes of Bacterial 1-Deoxy-d-xylulose 5-Phosphate Synthase.
Publication/Presentation Date
7-14-2017
Abstract
1-Deoxy-d-xylulose 5-phosphate (DXP) synthase catalyzes the thiamin diphosphate (ThDP)-dependent formation of DXP from pyruvate and d-glyceraldehyde 3-phosphate. DXP is at a metabolic branch point in bacteria, feeding into the methylerythritol phosphate pathway to indispensable isoprenoids and acting as a precursor for biosynthesis of essential cofactors in central metabolism, pyridoxal phosphate and ThDP, the latter of which is also required for DXP synthase catalysis. DXP synthase follows a unique random sequential mechanism and possesses an unusually large active site. These features have guided the design of sterically demanding alkylacetylphosphonates (alkylAPs) toward the development of selective DXP synthase inhibitors. alkylAPs studied here display selective, low μM inhibitory activity against DXP synthase. They are weak inhibitors of bacterial growth in standard nutrient rich conditions. However, bacteria are significantly sensitized to most alkylAPs in defined minimal growth medium, with minimal inhibitory concentrations (MICs) ranging from low μM to low mM and influenced by alkyl-chain length. The longest analog (C
Volume
3
Issue
7
First Page
467
Last Page
478
ISSN
2373-8227
Published In/Presented At
Sanders, S., Vierling, R. J., Bartee, D., DeColli, A. A., Harrison, M. J., Aklinski, J. L., Koppisch, A. T., & Freel Meyers, C. L. (2017). Challenges and Hallmarks of Establishing Alkylacetylphosphonates as Probes of Bacterial 1-Deoxy-d-xylulose 5-Phosphate Synthase. ACS infectious diseases, 3(7), 467–478. https://doi.org/10.1021/acsinfecdis.6b00168
Disciplines
Medicine and Health Sciences
PubMedID
28636325
Department(s)
Fellows and Residents
Document Type
Article