ChemInform Abstract: Reassignment of the Structure of the Antibiotic A53868 Reveals an Unusual Amino Dehydrophosphonic Acid.

Whitteck, John T.; Ni, Wei; Griffin, Benjamin M.; Eliot, Andrew C.; Thomas, Paul M.; Kelleher, Neil L.; Metcalf, William W.; Donk, Wilfred A. van der

doi:10.1002/chin.200814222

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“…Methyl acetylphosphonate (MAP), an indiscriminate inhibitor of ThDP-dependent enzymes, has been known to biochemists for decades 19 and to Nature for much longer; Streptomyces luridus produces the natural product dehydrophos, a peptidic prodrug of MAP (Figure 1). 20 As a tripeptide mimic, dehydrophos enters bacterial cells through the OppA peptide transporter, where it is then hydrolyzed by several intracellular peptidases to yield a phosphono-enamine intermediate which can spontaneously tautomerize to an imine and undergo hydrolysis to release MAP (Figure 1). 18 Dehydrophos exhibits growth inhibitory activity against bacteria, including E. coli, Bacillus subtilis, and Salmonella enterica, while MAP was shown to be inactive.…”

Section: ■ Resultsmentioning

confidence: 99%

Enamide Prodrugs of Acetyl Phosphonate Deoxy-d-xylulose-5-phosphate Synthase Inhibitors as Potent Antibacterial Agents

et al. 2019

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To fight the growing threat of antibiotic resistance, new antibiotics are required that target essential bacterial processes other than protein, DNA/RNA, and cell wall synthesis which constitute the majority of currently used antibiotics. 1-Deoxy-D-xylulose-5-phosphate (DXP) synthase is a vital enzyme in bacterial central metabolism feeding into the de novo synthesis of thiamine diphosphate (ThDP), pyridoxal phosphate (PLP), and essential isoprenoid precursors, isopentenyl diphosphate and dimethylallyl diphosphate. While potent and selective inhibitors of DXP synthase in vitro activity have been discovered, their antibacterial activity is modest. To improve the antibacterial activity of selective alkyl acetylphosphonate (alkylAP) inhibitors of DXP synthase, we have synthesized peptidic enamide prodrugs of alkylAPs inspired by the natural product dehydrophos, a prodrug of methyl acetylphosphonate. This prodrug strategy achieves dramatic increases in activity against Gram-negative pathogens for two alkylAPs, butyl acetylphosphonate and homopropargyl acetylphosphonate, decreasing MICs against E. coli by 33-and nearly 2000-fold, respectively. Antimicrobial studies and LC-MS/MS analysis of alkylAP-treated E. coli establish that the increased potency of prodrugs is due to increased accumulation of alkylAP inhibitors of DXP synthase via transport of the prodrug through the OppA peptide permease and subsequent amide hydrolysis. This work demonstrates the promise of targeting DXP synthase for the development of novel antibacterial agents.

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Section: ■ Resultsmentioning

confidence: 99%