Evidence map›Paper›PMID 41074856›Full record

ArticleProtein science : a publication of the Protein Society2025

Phosphate ions modulate enzyme activity and epistatic effects in two clavulanic acid-resistant β-lactamase mutants.

Marko Radojković, Saar F Koene, Aleksandra Chikunova, Bogdan I Florea, Sivanandam V Natarajan, Aimee L Boyle, Marcellus Ubbink

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Article in Protein science : a publication of the Protein Society, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.

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0cells of the map it votes in
2citing papers in PubMed
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1 · What the graph read from it

What it found

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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

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3 · Its place in the literature

Who cites it

2 citing papers in PubMed.

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4 · The record

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5 · Who and what money

Authors and funding

7 authors.

Marko RadojkovićLeiden Institute of Chemistry, Leiden University, Leiden, The Netherlands.
Saar F KoeneLeiden Institute of Chemistry, Leiden University, Leiden, The Netherlands.
Aleksandra ChikunovaLeiden Institute of Chemistry, Leiden University, Leiden, The Netherlands.
Bogdan I FloreaLeiden Institute of Chemistry, Leiden University, Leiden, The Netherlands.
Sivanandam V NatarajanLeiden Institute of Chemistry, Leiden University, Leiden, The Netherlands.
Aimee L BoyleLeiden Institute of Chemistry, Leiden University, Leiden, The Netherlands.
Marcellus UbbinkLeiden Institute of Chemistry, Leiden University, Leiden, The Netherlands.ORCID 0000-0002-2615-6914

Funding

Nederlandse Organisatie voor Wetenschappelijk Onderzoek 184.035.002Nederlandse Organisatie voor Wetenschappelijk Onderzoek ECHO 711.016.002Nederlandse Organisatie voor Wetenschappelijk Onderzoek OCENW.KLEIN.264
6 · The paper itself

Abstract

Epistasis, the non-additive effect of mutations, substantially undermines our ability to predict the evolutionary trajectories of enzymes. Epistatic effects are evident in the evolution of serine β-lactamases, where synergistic mutations can enhance antimicrobial resistance. We recently demonstrated that positive epistasis drives clavulanic acid resistance in double-mutant libraries of the β-lactamase BlaC. Here, we employed various biochemical and structural approaches to investigate molecular mechanisms underlying epistasis in the fitness of two double mutant variants, I105Y-S130G and I105G-G132N. For the latter enzyme, epistatic compensation of catalytic activity was detected for multiple substrates and proved to be highly buffer-dependent. Non-additive effects were also evident in the thermostability profile of the I105G-G132N variant. The interplay between the reduced clavulanic acid sensitivity of the S130G and G132N variants and active-site modifications induced by Ile105 substitutions is discussed. The results demonstrate that the origins of epistasis can be rooted in multiple enzyme traits, highlighting its important role in the evolution of antimicrobial resistance.

Indexed as

beta-LactamasesClavulanic AcidEpistasis, GeneticCatalytic DomainEscherichia coliMutationbeta-LactamasesClavulanic Acidantibiotic resistancebeta‐lactamaseclavulanic acidepistasis

Identifiers

PMID41074856
PMCPMC12514841

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.