4DE0

CTX-M-9 class A beta-lactamase complexed with compound 16

Summary for 4DE0

• Entry DOI: 10.2210/pdb4de0/pdb
• Related: 3G2Y 3G2Z 3G30 3G31 3G32 3G35 4DDS 4DDY 4DE0 4DE1 4DE3
• Descriptor: Beta-lactamase, N-[3-(1H-tetrazol-5-yl)phenyl]-1H-benzimidazole-7-carboxamide, DIMETHYL SULFOXIDE, ... (4 entities in total)
• Functional Keywords: ctx-m, hydrolase/hydrolase inhibitor, molecular docking, fragment, hydrolase-hydrolase inhibitor complex
• Biological source: Escherichia coli
• Total number of polymer chains: 2
• Total formula weight: 56599.65

Authors

Nichols, D.N.,Chen, Y. (deposition date: 2012-01-19, release date: 2012-03-28, Last modification date: 2024-11-06)

Primary citation

Nichols, D.A.,Jaishankar, P.,Larson, W.,Smith, E.,Liu, G.,Beyrouthy, R.,Bonnet, R.,Renslo, A.R.,Chen, Y.
Structure-Based Design of Potent and Ligand-Efficient Inhibitors of CTX-M Class A Beta-Lactamase
J.Med.Chem., 55:2163-2172, 2012

PubMed 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.

PubMed: 22296601
DOI: 10.1021/jm2014138

Experimental method

X-RAY DIFFRACTION (1.12 Å)