ArticleOrganic & biomolecular chemistry2016
Investigations on recyclisation and hydrolysis in avibactam mediated serine β-lactamase inhibition.
Article in Organic & biomolecular chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers, 1 of them a synthesis that pooled it.
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Who cites it
12 citing papers in PubMed, 1 synthesis or guideline pooled it, 29 citations in OpenAlex.
- Pharmacological aspects and spectrum of action of ceftazidime-avibactam: a systematic review.Infection · 2018Pooled it
- Structural perspectives on clinical β-lactamase inhibitors: From mechanism to resistance.Journal of microbiology (Seoul, Korea) · 2026Review
- Structural insights into the activity of carbapenemases: understanding the mechanism of action of current inhibitors and informing the design of new carbapenem adjuvants.RSC medicinal chemistry · 2025Review
- Drug Discovery in the Field of β-Lactams: An Academic Perspective.Antibiotics (Basel, Switzerland) · 2024Review
- Assessing the Potency of β-Lactamase Inhibitors with Diverse Inactivation Mechanisms against the PenA1 Carbapenemase fromACS infectious diseases · 2021Article
- Structural Investigations of the Inhibition of Escherichia coli AmpC β-Lactamase by Diazabicyclooctanes.Antimicrobial agents and chemotherapy · 2021Article
- Escape mutations circumvent a tradeoff between resistance to a beta-lactam and resistance to a beta-lactamase inhibitor.Nature communications · 2020Article
- Mechanism of proton transfer in class A β-lactamase catalysis and inhibition by avibactam.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Molecular Basis of Class A β-Lactamase Inhibition by Relebactam.Antimicrobial agents and chemotherapy · 2019Article
- Molecular Insights on the Release of Avibactam from the Acyl-Enzyme Complex.Biophysical journal · 2019Article
- Reversible inactivation of a peptidoglycan transpeptidase by a β-lactam antibiotic mediated by β-lactam-ring recyclization in the enzyme active site.Scientific reports · 2017Article
- Interaction of Avibactam with Class B Metallo-β-Lactamases.Antimicrobial agents and chemotherapy · 2016Article
Corrections and comments
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Authors and funding
4 authors at 4 institutions in 3 countries.
Funding
Abstract
β-Lactams inhibit penicillin-binding proteins (PBPs) and serine β-lactamases by acylation of a nucleophilic active site serine. Avibactam is approved for clinical use in combination with ceftazidime, and is a breakthrough non β-lactam β-lactamase inhibitor also reacting via serine acylation. Molecular dynamics (MD) and quantum chemical calculations on avibactam-mediated inhibition of a clinically relevant cephalosporinase reveal that recyclisation of the avibactam derived carbamoyl complex is favoured over hydrolysis. In contrast, we show that analogous recyclisation in β-lactam mediated inhibition is disfavoured. Avibactam recyclisation is promoted by a proton shuttle, a 'structural' water protonating the nucleophilic serine, and stabilization of the negative charge developed on aminocarbonyl oxygen. The results imply the potential of calculations for distinguishing between bifurcating pathways during inhibition and in generating hypotheses for predicting resistance. The inability of β-lactams to undergo recyclisation may be an Achilles heel, but one that can be addressed by suitably functionalized reversibly binding inhibitors.
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Registered trials
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