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Synthesis and Structural Analysis of a Novel Series of Non‐beta‐lactam Inhibitors of AmpC Beta‐lactamase
Author(s) -
Tomlinson Jenna Marie,
Mishra Uma J,
Kubiak Rachel L,
Schroeder William,
Davis Chris J,
Smart Robert P,
Powers Rachel A
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.792.2
Subject(s) - lactam , enzyme , chemistry , beta lactamase inhibitors , stereochemistry , cephalosporin , antibiotics , biochemistry , combinatorial chemistry
(‐lactams are the most widely prescribed class of antibiotics. However, their continued utility is threatened by the expression of (‐lactamase enzymes, which hydrolyze the defining lactam ring of these antibiotics, rendering them useless. Current clinical inhibitors for these enzymes also contain a lactam ring, allowing resistance to develop rapidly. Inhibitors that do not resemble (‐lactams would require bacteria to develop novel resistance mechanisms. Previous research identified a novel, non‐(‐lactam inhibitor for the class C (‐lactamase AmpC (3‐[(4‐chloroanilino)sulfonyl]thiophene‐2‐carboxylic acid; Ki 26 (M). In an effort to improve the binding affinity of this inhibitor, a series of sulfonylthiophene carboxylic acid derivatives were synthesized and tested for inhibition of AmpC. Several of these inhibitors were co‐crystallized with AmpC, and the structures of the complexes were determined using X‐ray crystallography.