Selective Trihydroxylated Azepane Inhibitors of NagZ, a Glycosidase Involved in Pseudomonas Aeruginosa Resistance to β-lactam Antibiotics

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 NHCOCF3 analog proved to be a selective inhibitor of NagZ over other glucosaminidases including human OGA and lysosomal hexosaminidases HexA and B.The synthesis of a series of D-gluco-like configured4,5,6-trihydroxyazepanes bearing a triazole, a sulfonamide or a fluorinatedacetamide moiety at C-3 is described. These synthetic derivatives have beentested for their ability to selectively inhibit the muropeptide recyclingglucosaminidase NagZ and to thereby increase sensitivity of Pseudomonasaeruginosa to β-lactams, a pathway with substantial therapeutic potential.While introduction of triazole and sulfamide groups failed to lead toglucosaminidase inhibitors, the NHCOCF3 analog proved to be a selectiveinhibitor of NagZ over other glucosaminidases including human OGA andlysosomal hexosaminidases HexA and B