Selective trihydroxylated azepane inhibitors of NagZ, a glycosidase involved in Pseudomonas aeruginosa resistance to β-lactam antibiotics

• Published in: Organic & biomolecular chemistry 2017, Vol.15 (21), p.4609-4619
• Main Authors: Bouquet, J, King, D T, Vadlamani, G, Benzie, G R, Iorga, B, Ide, D, Adachi, I, Kato, A, Vocadlo, D J, Mark, B L, Blériot, Y, Désiré, J
• Format: Article
• Language: English
• Subjects: Anti-Bacterial Agents - pharmacology; Azepines - chemical synthesis; Azepines - chemistry; Azepines - metabolism; Azepines - pharmacology; Bacteriology; beta-Lactams - pharmacology; Biochemistry, Molecular Biology; Ceftazidime - pharmacology; Chemical Sciences; Drug Synergism; Glycoside Hydrolases - antagonists & inhibitors; Glycoside Hydrolases - chemistry; Glycoside Hydrolases - metabolism; Hydroxylation; Life Sciences; Medicinal Chemistry; Microbiology and Parasitology; Molecular Docking Simulation; Protein Conformation; Pseudomonas aeruginosa; Pseudomonas aeruginosa - drug effects; Pseudomonas aeruginosa - enzymology; Structural Biology
• ISSN: 1477-0520; 1477-0539
• DOI: 10.1039/c7ob00838d

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 β-lactams, a pathway with substantial therapeutic potential. While introduction of triazole and sulfamide groups failed to lead to glucosaminidase inhibitors, the NHCOCF analog proved to be a selective inhibitor of NagZ over other glucosaminidases including human O-GlcNAcase and lysosomal hexosaminidases HexA and B.