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

Resource type
Date created
2017-05-09
Authors/Contributors
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 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
Document
Identifier
DOI: 10.1039/C7OB00838D
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
Publication title
Org. Biomol. Chem.
Document title
Selective Trihydroxylated Azepane Inhibitors of NagZ, a Glycosidase Involved in Pseudomonas Aeruginosa Resistance to β-lactam Antibiotics
Date
2017
Volume
15
Issue
21
First page
4609
Last page
4619
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Copyright is held by the author(s).
Scholarly level
Peer reviewed?
Yes
Language