Synthesis and Evaluation of Fluoroalkyl Phosphonyl Analogues of 2- C-Methylerythritol Phosphate as Substrates and Inhibitors of IspD from Human Pathogens.
David BarteeMichael J WheadonCaren L Freel MeyersPublished in: The Journal of organic chemistry (2018)
Targeting 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.
Keyphrases
- escherichia coli
- cell wall
- gram negative
- mycobacterium tuberculosis
- endothelial cells
- plasmodium falciparum
- molecular docking
- staphylococcus aureus
- antimicrobial resistance
- pluripotent stem cells
- multidrug resistant
- amino acid
- structure activity relationship
- biofilm formation
- gene expression
- single cell
- klebsiella pneumoniae
- dna methylation
- cancer therapy
- climate change
- pseudomonas aeruginosa