ABSTRACT
The synthesis of a series of d-gluco-like configured 4,5,6-trihydroxyazepanes bearing a triazole, a sulfonamide or a fluorinated acetamide moiety at C-3 is described. These synthetic derivatives have been tested for their ability to selectively inhibit the muropeptide recycling glucosaminidase NagZ and to thereby increase sensitivity of Pseudomonas aeruginosa to ß-lactams, a pathway with substantial therapeutic potential. While introduction of triazole and sulfamide groups failed to lead to glucosaminidase inhibitors, the NHCOCF3 analog proved to be a selective inhibitor of NagZ over other glucosaminidases including human O-GlcNAcase and lysosomal hexosaminidases HexA and B.
Subject(s)
Anti-Bacterial Agents/pharmacology , Azepines/chemistry , Azepines/pharmacology , Glycoside Hydrolases/antagonists & inhibitors , Pseudomonas aeruginosa/drug effects , Pseudomonas aeruginosa/enzymology , beta-Lactams/pharmacology , Azepines/chemical synthesis , Azepines/metabolism , Ceftazidime/pharmacology , Drug Synergism , Glycoside Hydrolases/chemistry , Glycoside Hydrolases/metabolism , Hydroxylation , Molecular Docking Simulation , Protein ConformationABSTRACT
Mono-, di- and trisaccharide derivatives of 1,2-unsaturated N-acetyl-d-glucal have been synthesized and shown to function as tight-binding inhibitors/slow substrates of representative hexosaminidases. Turnover is slow and not observed in the thioamide analogue, allowing determination of the 3-dimensional structure of the complex. Inhibition is insensitive to pH and to mutation of key catalytic residues, consistent with the uncharged character of the inhibitor. These properties could render this inhibitor class less prone to development of resistance.
