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Synthesis and Evaluation of Fluoroalkyl Phosphonyl Analogues of 2‑C‑Methylerythritol Phosphate as Substrates and Inhibitors of IspD from Human Pathogens
journal contribution
posted on 2018-06-05, 00:00 authored by David Bartee, Michael J. Wheadon, Caren L. Freel MeyersTargeting essential bacterial processes
beyond cell wall, protein,
nucleotide, and folate syntheses holds promise to reveal new antimicrobial
agents and expand the potential drugs available for combination therapies.
The synthesis of isoprenoid precursors, isopentenyl diphosphate (IDP)
and dimethylallyl diphosphate (DMADP), is vital for all organisms;
however, humans use the mevalonate pathway for production of IDP/DMADP
while many pathogens, including Plasmodium falciparum and Mycobacterium tuberculosis, use the orthogonal
methylerythritol phosphate (MEP) pathway. Toward developing novel
antimicrobial agents, we have designed and synthesized a series of
phosphonyl analogues of MEP and evaluated their abilities to interact
with IspD, both as inhibitors of the natural reaction and as antimetabolite
alternative substrates that could be processed enzymatically to form
stable phosphonyl analogues as potential inhibitors of downstream
MEP pathway intermediates. In this compound series, the S-monofluoro MEP analogue displays the most potent inhibitory activity
against Escherichia coli IspD and is the best substrate
for both the E. coli and P. falciparum IspD orthologues with a Km approaching
that of the natural substrate for the E. coli enzyme.
This work represents a first step toward the development of phosphonyl
MEP antimetabolites to modulate early isoprenoid biosynthesis in human
pathogens.
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Human Pathogens Targetingantimetabolite alternative substratesmonofluoro MEP analogue displaysdiphosphatefalciparum IspD orthologuesseriesphosphonyl analoguesnovel antimicrobial agentsIDPDMADPpathogenFluoroalkyl Phosphonyl AnaloguesEscherichia coli IspDinhibitorphosphonyl MEP antimetabolitesMEP pathway intermediatesisoprenoidorthogonal methylerythritol phosphate
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