ArticleAntimicrobial agents and chemotherapy2011
Importance of position 170 in the inhibition of GES-type β-lactamases by clavulanic acid.
Article in Antimicrobial agents and chemotherapy, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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13 citing papers in PubMed, 24 citations in OpenAlex.
- Capillary Isoelectric Focusing of Proteins and Peptides Using an In-Line cIEF-ESI Interface with Improved MS Characteristics.Analytical chemistry · 2025Article
- Restricted Rotational Flexibility of the C5α-Methyl-Substituted Carbapenem NA-1-157 Leads to Potent Inhibition of the GES-5 Carbapenemase.ACS infectious diseases · 2024Article
- Unveiling the structural features that regulate carbapenem deacylation in KPC-2 through QM/MM and interpretable machine learning.Physical chemistry chemical physics : PCCP · 2023Article
- Imipenem/Relebactam Resistance in Clinical Isolates of Extensively Drug Resistant Pseudomonas aeruginosa: Inhibitor-Resistant β-Lactamases and Their Increasing Importance.Antimicrobial agents and chemotherapy · 2022Article
- Laboratory Variants GESAntimicrobial agents and chemotherapy · 2021Article
- Sequence heterogeneity of the PenA carbapenemase in clinical isolates of Burkholderia multivorans.Diagnostic microbiology and infectious disease · 2018Article
- P174E Substitution in GES-1 and GES-5 β-Lactamases Improves Catalytic Efficiency toward Carbapenems.Antimicrobial agents and chemotherapy · 2018Article
- Structural and Functional Aspects of Class A Carbapenemases.Current drug targets · 2016Review
- The intrinsic resistome of bacterial pathogens.Frontiers in microbiology · 2013Article
- GES-18, a new carbapenem-hydrolyzing GES-Type β-lactamase from Pseudomonas aeruginosa that contains Ile80 and Ser170 residues.Antimicrobial agents and chemotherapy · 2013Article
- Substitutions at position 105 in SHV family β-lactamases decrease catalytic efficiency and cause inhibitor resistance.Antimicrobial agents and chemotherapy · 2012Article
- Kinetic and crystallographic studies of extended-spectrum GES-11, GES-12, and GES-14 β-lactamases.Antimicrobial agents and chemotherapy · 2012Article
- The class A β-lactamase FTU-1 is native to Francisella tularensis.Antimicrobial agents and chemotherapy · 2012Article
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5 authors at 1 institution in 1 country.
Funding
Abstract
Bacterial resistance to β-lactam antibiotics (penicillins, cephalosporins, carbapenems, etc.) is commonly the result of the production of β-lactamases. The emergence of β-lactamases capable of turning over carbapenem antibiotics is of great concern, since these are often considered the last resort antibiotics in the treatment of life-threatening infections. β-Lactamases of the GES family are extended-spectrum enzymes that include members that have acquired carbapenemase activity through a single amino acid substitution at position 170. We investigated inhibition of the GES-1, -2, and -5 β-lactamases by the clinically important β-lactamase inhibitor clavulanic acid. While GES-1 and -5 are susceptible to inhibition by clavulanic acid, GES-2 shows the greatest susceptibility. This is the only variant to possess the canonical asparagine at position 170. The enzyme with asparagine, as opposed to glycine (GES-1) or serine (GES-5), then leads to a higher affinity for clavulanic acid (K(i) = 5 μM), a higher rate constant for inhibition, and a lower partition ratio (r ≈ 20). Asparagine at position 170 also results in the formation of stable complexes, such as a cross-linked species and a hydrated aldehyde. In contrast, serine at position 170 leads to formation of a long-lived trans-enamine species. These studies provide new insight into the importance of the residue at position 170 in determining the susceptibility of GES enzymes to clavulanic acid.
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