What question did this study set out to answer?

To examine how residue substitutions at the Ambler position 105 gatekeeper site affect inhibitor-resistant phenotypes across class A β-lactamases.

June 6, 2025Journal of Biological ChemistryOpen Access

A glycine at position 105 leads to clavulanic acid and avibactam resistance in class A β-lactamases

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Authors

MRMarko RadojkovićLeiden University ACAleksandra ChikunovaLeiden University SKSaar F. Koene

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Implication

Mutational profiling study reveals position 105 substitutions drive clavulanic acid and avibactam resistance in class A beta-lactamases, highlighting a critical hotspot for inhibitor design.

Key Points

To examine how residue substitutions at the Ambler position 105 gatekeeper site affect inhibitor-resistant phenotypes across class A β-lactamases.
Performed site-saturation mutagenesis targeting Ambler position 105 across five distinct class A β-lactamases.
Conducted extensive fitness profiling and inhibitor susceptibility screening of variants using deep sequencing.
Inhibitor resistance emerged across variants, with glycine and arginine substitutions at position 105 conferring the greatest reduction in inhibitor susceptibility.
The Ile105Arg mutation in BlaC simultaneously enhanced carbenicillin degradation and enabled evasion of clavulanic acid inhibition.
The Y105G mutation in CTX-M-14 and TEM-1 markedly decreased in vitro sensitivity to avibactam by increasing conformational flexibility of the inhibitor within the active site.

Cite This Study

Radojković et al. (2025) studied this question.

synapsesocial.com/papers/6a19fe1605af093a17f6da10 https://doi.org/10.1016/j.jbc.2025.110347

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Implication

Mutational profiling study reveals position 105 substitutions drive clavulanic acid and avibactam resistance in class A beta-lactamases, highlighting a critical hotspot for inhibitor design.

A glycine at position 105 leads to clavulanic acid and avibactam resistance in class A β-lactamases

Discussion

Member takes

Implication

Key Points

Cite This Study

A glycine at position 105 leads to clavulanic acid and avibactam resistance in class A β-lactamases

Discussion

Member takes

Implication

Key Points

Cite This Study

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