ArticleScientific reports2016
Deep Sequencing of Random Mutant Libraries Reveals the Active Site of the Narrow Specificity CphA Metallo-β-Lactamase is Fragile to Mutations.
Article in Scientific reports, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed.
- Mutations inMicrobiology spectrum · 2025Article
- Mapping the determinants of catalysis and substrate specificity of the antibiotic resistance enzyme CTX-M β-lactamase.Communications biology · 2023Article
- Article
- Metallo-β-lactamases in the Age of Multidrug Resistance: From Structure and Mechanism to Evolution, Dissemination, and Inhibitor Design.Chemical reviews · 2021Review
- Mutational Effects on Carbapenem Hydrolysis of YEM-1, a New Subclass B2 Metallo-β-Lactamase from Yersinia mollaretii.Antimicrobial agents and chemotherapy · 2020Article
- Broad spectrum antibiotic-degrading metallo-β-lactamases are phylogenetically diverse.Protein & cell · 2020Article
- Identifying Oxacillinase-48 Carbapenemase Inhibitors Using DNA-Encoded Chemical Libraries.ACS infectious diseases · 2020Article
- Differential active site requirements for NDM-1 β-lactamase hydrolysis of carbapenem versus penicillin and cephalosporin antibiotics.Nature communications · 2018Article
- Shaping Substrate Selectivity in a Broad-Spectrum Metallo-β-Lactamase.Antimicrobial agents and chemotherapy · 2018Article
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5 authors.
Funding
Abstract
CphA is a Zn(2+)-dependent metallo-β-lactamase that efficiently hydrolyzes only carbapenem antibiotics. To understand the sequence requirements for CphA function, single codon random mutant libraries were constructed for residues in and near the active site and mutants were selected for E. coli growth on increasing concentrations of imipenem, a carbapenem antibiotic. At high concentrations of imipenem that select for phenotypically wild-type mutants, the active-site residues exhibit stringent sequence requirements in that nearly all residues in positions that contact zinc, the substrate, or the catalytic water do not tolerate amino acid substitutions. In addition, at high imipenem concentrations a number of residues that do not directly contact zinc or substrate are also essential and do not tolerate substitutions. Biochemical analysis confirmed that amino acid substitutions at essential positions decreased the stability or catalytic activity of the CphA enzyme. Therefore, the CphA active - site is fragile to substitutions, suggesting active-site residues are optimized for imipenem hydrolysis. These results also suggest that resistance to inhibitors targeted to the CphA active site would be slow to develop because of the strong sequence constraints on function.
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