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Antibiotic resistance is a major public health concern that arises when bacteria evolve mechanisms to withstand the effects of antibiotic treatments. This resistance can be intrinsic, acquired through genetic mutations, or transferred between bacteria via horizontal gene transfer. The development of antibiotic resistance poses significant challenges in treating bacterial infections and necessitates ongoing research to develop new therapeutic strategies.Intrinsic resistance occurs when bacterial...
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Updated: Nov 7, 2025

Testing the Role of Multicopy Plasmids in the Evolution of Antibiotic Resistance
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Cryptic β-Lactamase Evolution Is Driven by Low β-Lactam Concentrations.

Christopher Fröhlich1, João A Gama2, Klaus Harms2

  • 1The Norwegian Structural Biology Centre (NorStruct), Department of Chemistry, UiT The Arctic University of Norway, Tromsø, Norway christofrohlich@gmail.com hanna-kirsti.leiros@uit.no.

Msphere
|April 29, 2021
PubMed
Summary

Low antibiotic concentrations drive the evolution of beta-lactamases, like OXA-48, by increasing their diversity and fitness. These cryptic changes act as stepping stones toward clinical antimicrobial resistance.

Keywords:
Escherichia coliOXA-48carbapenemcarbapenemasecatalytic efficiencyceftazidimecryptic evolutionresistance developmentstructural flexibilitysub-MIC

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Area of Science:

  • Microbiology
  • Evolutionary Biology
  • Biochemistry

Background:

  • Understanding how low antibiotic concentrations influence antimicrobial resistance evolution is crucial.
  • The role of sub-inhibitory concentrations of beta-lactams in driving resistance, particularly for beta-lactamases like OXA-48, remains understudied.

Purpose of the Study:

  • To investigate the evolutionary impact of low ceftazidime concentrations on the carbapenemase OXA-48.
  • To test the hypothesis that low antibiotic levels promote genetic diversity that can lead to clinical resistance.

Main Methods:

  • Experimental evolution of *Escherichia coli* expressing *bla*OXA-48 at sub-minimum inhibitory concentrations (sub-MICs) of ceftazidime.
  • Identification and characterization of OXA-48 variants.
  • Assessment of susceptibility profiles, dose-response curves, and catalytic efficiencies.

Main Results:

  • Seven single variants of OXA-48 were identified, conferring only marginal increases in resistance.
  • These variants exhibited significant selectable fitness benefits in competition experiments at sub-MICs.
  • Variants showed enhanced catalytic efficiencies toward ceftazidime, linked to structural changes in key loops and active site residues.

Conclusions:

  • Low-level beta-lactam concentrations can drive beta-lactamase evolution through cryptic phenotypes.
  • This process generates standing genetic diversity that can be selected for under increased antibiotic pressure, contributing to clinical resistance.