Structure-Based Enhancement of Boronic Acid-Based Inhibitors of AmpC β-Lactamase

• Published in: Journal of medicinal chemistry 1998-11, Vol.41 (23), p.4577-4586
• Main Authors: Weston, G. Scott, Blázquez, Jesús, Baquero, Fernando, Shoichet, Brian K
• Format: Article
• Language: English
• Subjects: Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - metabolism; Anti-Bacterial Agents - pharmacology; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Bacterial Proteins; beta-Lactam Resistance; beta-Lactamase Inhibitors; beta-Lactamases - metabolism; Binding Sites; Biological and medical sciences; Boronic Acids - chemistry; Crystallography, X-Ray; Drug Synergism; Enterobacter cloacae - drug effects; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - metabolism; Enzyme Inhibitors - pharmacology; Escherichia coli - drug effects; Escherichia coli - enzymology; Medical sciences; Microbial Sensitivity Tests; Models, Molecular; Pharmacology. Drug treatments; Structure-Activity Relationship; Thiophenes
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm980343w

The expression of β-lactamases is the most common form of bacterial resistance to β-lactam antibiotics. To combat these enzymes, agents that inhibit (e.g. clavulanic acid) or evade (e.g. aztreonam) β-lactamases have been developed. Both the β-lactamase inhibitors and the β-lactamase-resistant antibiotics are themselves β-lactams, and bacteria have responded to these compounds by expressing variant enzymes resistant to inhibition (e.g. IRT-3) or that inactivate the β-lactamase-resistant antibiotic (e.g. TEM-10). Moreover, these compounds have increased the frequency of bacteria with intrinsically resistant β-lactamases (e.g. AmpC). In an effort to identify non-β-lactam-based β-lactamase inhibitors, we used the crystallographic structure of the m-aminophenylboronic acid−Escherichia coli AmpC β-lactamase complex to suggest modifications that might enhance the affinity of boronic acid-based inhibitors for class C β-lactamases. Several types of compounds were modeled into the AmpC binding site, and a total of 37 boronic acids were ultimately tested for β-lactamase inhibition. The most potent of these compounds, benzo[b]thiophene-2-boronic acid (36), has an affinity for E. coli AmpC of 27 nM. The wide range of functionality represented by these compounds allows for the steric and chemical “mapping” of the AmpC active site in the region of the catalytic Ser64 residue, which may be useful in subsequent inhibitor discovery efforts. Also, the new boronic acid-based inhibitors were found to potentiate the activity of β-lactam antibiotics, such as amoxicillin and ceftazidime, against bacteria expressing class C β-lactamases. This suggests that boronic acid-based compounds may serve as leads for the development of therapeutic agents for the treatment of β-lactam-resistant infections.