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

Peer reviewed: 
Yes, item is peer reviewed.
Scholarly level: 
Faculty/Staff
Final version published as: 

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. (2017). Selective trihydroxylated azepane inhibitors of NagZ, a glycosidase involved in Pseudomonas aeruginosa resistance to β-lactam antibiotics. Org. Biomol. Chem., 15(21), 4609–4619. https://doi.org/10.1039/C7OB00838D

Date created: 
2017-05-09
Identifier: 
DOI: 10.1039/C7OB00838D
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 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 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

 

Language: 
English
Document type: 
Article
Rights: 
Rights remain with the authors.
File(s): 
Statistics: