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Insertion sequence transposition determines imipenem resistance in Acinetobacter baumannii.

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Imipenem exposure in Acinetobacter baumannii causes ISAba1 transposition, leading to blaOXA-95 gene overexpression and carbapenem resistance. This mechanism is crucial for understanding antibiotic resistance in this pathogen.

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Area of Science:

  • Microbiology
  • Genetics
  • Molecular Biology

Background:

  • Acinetobacter baumannii is a significant opportunistic pathogen known for its increasing antibiotic resistance.
  • Carbapenem antibiotics, including imipenem, are critical for treating A. baumannii infections.
  • Understanding the mechanisms of imipenem resistance is essential for developing effective therapeutic strategies.

Purpose of the Study:

  • To investigate the genomic mechanisms of imipenem resistance in Acinetobacter baumannii.
  • To identify genetic alterations responsible for phenotypic resistance following imipenem exposure.

Main Methods:

  • Multistep selection of imipenem-resistant mutants from a susceptible A. baumannii strain (ATCC 17978).
  • Antibiotic susceptibility testing and confirmation of mutants by pulsed-field gel electrophoresis.
  • Whole-genome sequencing of resistant mutants and PCR for genetic recombination confirmation.
  • Quantitative PCR to analyze blaOXA-95 gene expression.

Main Results:

  • Phenotypic resistance to carbapenems was observed in selected mutants.
  • Genomewide analysis revealed ISAba1 transposition upstream of the blaOXA-95 gene in all imipenem-selected mutants.
  • Imipenem exposure (≥0.5 mg/L) induced ISAba1 transposition.
  • A 200-fold increase in blaOXA-95 gene expression was detected, correlating with imipenem resistance.

Conclusions:

  • Imipenem exposure at 0.5 mg/L triggers ISAba1 transposition upstream of blaOXA-95.
  • Overexpression of blaOXA-95, mediated by ISAba1 transposition, is a key mechanism of imipenem resistance in A. baumannii.
  • This finding provides critical insights into carbapenem resistance development in A. baumannii.