%0 Journal Article %J Chembiochem %D 2015 %T Direct Staudinger-Phosphonite Reaction Provides Methylphosphonamidates as Inhibitors of CE4 De-N-acetylases. %A Ariyakumaran, Rishikesh %A Pokrovskaya, Varvara %A Little, Dustin J %A Howell, P Lynne %A Nitz, Mark %K Acetylglucosamine %K Amidohydrolases %K Bacterial Proteins %K Enzyme Inhibitors %K Escherichia coli %K Escherichia coli Infections %K Escherichia coli Proteins %K Humans %K Methylation %K Organophosphorus Compounds %K Peptidoglycan %K Pneumococcal Infections %K Streptococcus pneumoniae %X

De-N-acetylases of β-(1→6)-D-N-acetylglucosamine polymers (PNAG) and β-(1→4)-D-N-acetylglucosamine residues in peptidoglycan are attractive targets for antimicrobial agents. PNAG de-N-acetylases are necessary for biofilm formation in numerous pathogenic bacteria. Peptidoglycan de-N-acetylation facilitates bacterial evasion of innate immune defenses. To target these enzymes, transition-state analogue inhibitors containing a methylphosphonamidate have been synthesized through a direct Staudinger-phosphonite reaction. The inhibitors were tested on purified PgaB, a PNAG de-N-acetylase from Escherichia coli, and PgdA, a peptidoglycan de-N-acetylase from Streptococcus pneumonia. Herein, we describe the most potent inhibitor of peptidoglycan de-N-acetylases reported to date (Ki =80 μM). The minimal inhibition of PgaB observed provides insight into key structural and functional differences in these enzymes that will need to be considered during the development of future inhibitors.

%B Chembiochem %V 16 %P 1350-6 %8 2015 Jun 15 %G eng %N 9 %1 http://www.ncbi.nlm.nih.gov/pubmed/25864869?dopt=Abstract %R 10.1002/cbic.201500091