title: Structure-based design of potent and ligand-efficient inhibitors of CTX-M class A β-lactamase.
abstract: The emergence of CTX-M class A extended-spectrum β-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 μM) 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 β-lactamase. Their complex crystal structures provide valuable information about ligand binding for future inhibitor design.
authors.affiliation: University of South Florida College of Medicine, Department of Molecular Medicine, 12901 Bruce B. Downs Boulevard, MDC 3522, Tampa, Florida 33612, USA.
authors.forename: Derek A
authors.initials: DA
authors.lastname: Nichols
authors.forename: Priyadarshini
authors.initials: P
authors.lastname: Jaishankar
authors.forename: Wayne
authors.initials: W
authors.lastname: Larson
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Smith
authors.forename: Guoqing
authors.initials: G
authors.lastname: Liu
authors.forename: Racha
authors.initials: R
authors.lastname: Beyrouthy
authors.forename: Richard
authors.initials: R
authors.lastname: Bonnet
authors.forename: Adam R
authors.initials: AR
authors.lastname: Renslo
authors.forename: Yu
authors.initials: Y
authors.lastname: Chen
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D002439:Cefotaxime / Q000494:pharmacology; D018360:Crystallography, X-Ray; D024881:Drug Resistance, Bacterial; D004357:Drug Synergism; D004926:Escherichia coli / Q000187:drug effects; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D065093:beta-Lactamase Inhibitors
chemical_list: C573290:6-trifluoromethyl-3H-benzoimidazole-4-carboxylic acid (3-(1H-tetrazol-5-yl)-phenyl)amide; D000900:Anti-Bacterial Agents; D001562:Benzimidazoles; D008024:Ligands; D013777:Tetrazoles; D065093:beta-Lactamase Inhibitors; D002439:Cefotaxime