ArticleJournal of the American Chemical Society2022
β-Lactamases Evolve against Antibiotics by Acquiring Large Active-Site Electric Fields.
Article in Journal of the American Chemical Society, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
What it found
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Who cites it
11 citing papers in PubMed, 32 citations in OpenAlex.
- Photoisomerization detected in a fully wavelength-tunable rhodopsin mimic system.Acta crystallographica. Section D, Structural biology · 2026Article
- Electrostatic atlas of non-covalent interactions built into metal-organic frameworks.Nature chemistry · 2025Article
- Effect of Mutations on the Evolution of Extended Spectrum β-lactamases (ESBL).The protein journal · 2025Review
- Electric-Field Catalysis on Carbon Nanotubes in Electromicrofluidic Reactors: Monoterpene Cyclizations.Angewandte Chemie (International ed. in English) · 2025Article
- Carbapenem-induced β-lactamase-isoform expression trends in Acinetobacter baumannii.Scientific reports · 2024Article
- The Evolution of the Acylation Mechanism inACS catalysis · 2024Article
- Electric Fields Are a Key Determinant of Carbapenemase Activity in Class A β-Lactamases.ACS catalysis · 2024Article
- Critical Evaluation of Polarizable and Nonpolarizable Force Fields for Proteins Using Experimentally Derived Nitrile Electric Fields.Journal of the American Chemical Society · 2024Article
- Key interaction networks: Identifying evolutionarily conserved non-covalent interaction networks across protein families.Protein science : a publication of the Protein Society · 2024Article
- Review
- Direct measurements of biomolecular electrostatics through experiments.Current opinion in structural biology · 2023Review
Corrections and comments
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
A compound bound covalently to an enzyme active site can act either as a substrate if the covalent linkage is readily broken up by the enzyme or as an inhibitor if the bond dissociates slowly. We tracked the reactivity of such bonds associated with the rise of the resistance to penicillin G (PenG) in protein evolution from penicillin-binding proteins (PBPs) to TEM β-lactamases and with the development of avibactam (Avb) to overcome the resistance. We found that the ester linkage in PBP-PenG is resistant to hydrolysis mainly due to the small electric fields present in the protein active site. Conversely, the same linkage in the descendant TEM-PenG experiences large electric fields that stabilize the more charge-separated transition state and thus lower the free energy barrier to hydrolysis. Specifically, the electric fields were improved from -59 to -140 MV/cm in an ancient evolution dating back billions of years, contributing 5 orders of magnitude rate acceleration. This trend continues today in the nullification of newly developed antibiotic drugs. The fast linkage hydrolysis acquired from evolution is counteracted by the upgrade of PenG to Avb whose linkage escapes from the hydrolysis by returning to a low-field environment. Using the framework of electrostatic catalysis, the electric field, an observable from vibrational spectroscopy, provides a unifying physical metric to understand protein evolution and to guide the design of covalent drugs.
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Registered trials
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