title: Direct Staudinger-Phosphonite Reaction Provides Methylphosphonamidates as Inhibitors of CE4 De-N-acetylases.
abstract: 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.
authors: Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario, M5S 3H6 (Canada).
authors: Rishikesh
authors: R
authors: Ariyakumaran
authors: Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario, M5S 3H6 (Canada).
authors: Varvara
authors: V
authors: Pokrovskaya
authors: Program in Molecular Structure and Function, The Hospital for Sick Children and Department of Biochemistry, University of Toronto, 555 University Avenue, Toronto, Ontario M5G 1X8 (Canada).
authors: Dustin J
authors: DJ
authors: Little
authors: Program in Molecular Structure and Function, The Hospital for Sick Children and Department of Biochemistry, University of Toronto, 555 University Avenue, Toronto, Ontario M5G 1X8 (Canada).
authors: P Lynne
authors: PL
authors: Howell
authors: Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario, M5S 3H6 (Canada). mnitz@chem.utoronto.ca.
authors: Mark
authors: M
authors: Nitz
mesh_terms: D000117:Acetylglucosamine / Q000378:metabolism; D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology*; D004927:Escherichia coli Infections / Q000188:drug therapy / Q000382:microbiology; D029968:Escherichia coli Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008745:Methylation; D009943:Organophosphorus Compounds / Q000737:chemistry / Q000494:pharmacology*; D010457:Peptidoglycan / Q000378:metabolism; D011008:Pneumococcal Infections / Q000188:drug therapy / Q000382:microbiology; D013296:Streptococcus pneumoniae / Q000187:drug effects / Q000201:enzymology*
chemical_list: D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D029968:Escherichia coli Proteins; D009943:Organophosphorus Compounds; D010457:Peptidoglycan; D000581:Amidohydrolases; C575184:poly-beta-1,6-N-acetyl-D-glucosamine de-N-acetylase, E coli; C411846:pgdA protein, Streptococcus pneumoniae; D000117:Acetylglucosamine
keywords: Staudinger reaction; de-N-acetylase; inhibitors; methylphosphonamidate; transition states