Abstract
BackgroundblaVEB-1 is an integron-located extended-spectrum β-lactamase gene initially detected in Escherichia coli and Pseudomonas aeruginosa strains from south-east Asia. Several recent studies have reported that VEB-1-positive strains are highly resistant to ceftazidime, cefotaxime and aztreonam antibiotics. One strategy to overcome resistance involves administering antibiotics together with β-lactamase inhibitors during the treatment of infectious diseases. During this study, four VEB-1 β-lactamase inhibitors were identified using computer-aided drug design.MethodsThe SWISS-MODEL tool was utilized to generate three dimensional structures of VEB-1 β-lactamase, and the 3D model VEB-1 was verified using PROCHECK, ERRAT and VERIFY 3D programs. Virtual screening was performed by docking inhibitors obtained from the ZINC Database to the active site of the VEB-1 protein using AutoDock Vina software.Results and conclusionHomology modeling studies were performed to obtain a three-dimensional structure of VEB-1 β-lactamase. The generated model was validated, and virtual screening of a large chemical ligand library with docking simulations was performed using AutoDock software with the ZINC database. On the basis of the dock-score, four molecules were subjected to ADME/TOX analysis, with ZINC4085364 emerging as the most potent inhibitor of the VEB-1 β-lactamase.
Highlights
BlaVEB-1 is an integron-located extended-spectrum β-lactamase gene initially detected in Escherichia coli and Pseudomonas aeruginosa strains from southeast Asia
This study identified 950 compounds that were structurally similar to available Amber class A β-lactamase inhibitors during screening
Protein homology modeling and validation Multiple sequence alignment of VEB-1 with PER-1, CTX-M-16 and Toho-1 β-lactamases demonstrated that VEB-1 is highly homologous to PER-1 type β-lactamases (38% sequence identity) (Figure 1A)
Summary
BlaVEB-1 is an integron-located extended-spectrum β-lactamase gene initially detected in Escherichia coli and Pseudomonas aeruginosa strains from southeast Asia. Several recent studies have reported that VEB-1-positive strains are highly resistant to ceftazidime, cefotaxime and aztreonam antibiotics. P. aeruginosa isolates producing the VEB-1a variant, which differs from VEB-1 by only a single amino acid located in the leader peptide of the pre-mature protein, have been identified in Kuwait and India [11,12]. VEB-1 has high amino-acid identity to PER-1 and PER-2 (38%) EBSLs, and confers high-level resistance to ceftazidime, cefotaxime and aztreonam [13]. Rather than having a typical class 1 integron structure, in these isolates blaVEB-1 is flanked by identical 135-bp sequences, termed repeated elements (Res), which are bracketed by two truncated 30-conserved class 1 integron sequences in direct repeat [14]
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