Structure-based design of potent and ligand-efficient inhibitors of CTX-M class A beta-lactamase.
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Nichols DA, Jaishankar P, Larson W, Smith E, Liu G, Beyrouthy R, Bonnet R, Renslo AR, Chen Y
Structure-based design of potent and ligand-efficient inhibitors of CTX-M class A beta-lactamase.
J Med Chem. 2012 Mar 8;55(5):2163-72. doi: 10.1021/jm2014138. Epub 2012 Feb 14.
- PubMed ID
- 22296601 [ View in PubMed]
- Abstract
The emergence of CTX-M class A extended-spectrum beta-lactamases poses a serious health threat to the public. We have applied structure-based design to improve the potency of a novel noncovalent tetrazole-containing CTX-M inhibitor (K(i) = 21 muM) more than 200-fold via structural modifications targeting two binding hot spots, a hydrophobic shelf formed by Pro167 and a polar site anchored by Asp240. Functional groups contacting each binding hot spot independently in initial designs were later combined to produce analogues with submicromolar potencies, including 6-trifluoromethyl-3H-benzoimidazole-4-carboxylic acid [3-(1H-tetrazol-5-yl)-phenyl]-amide, which had a K(i) value of 89 nM and reduced the MIC of cefotaxime by 64-fold in CTX-M-9 expressing Escherichia coli . The in vitro potency gains were accompanied by improvements in ligand efficiency (from 0.30 to 0.39) and LipE (from 1.37 to 3.86). These new analogues represent the first nM-affinity noncovalent inhibitors of a class A beta-lactamase. Their complex crystal structures provide valuable information about ligand binding for future inhibitor design.