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Meropenem resistance in Pseudomonas aeruginosa

Y Sumita1, M Fukasawa

  • 1Discovery Research Laboratories III, Sumitomo Pharmaceuticals, Osaka, Japan.

Chemotherapy
|January 1, 1996
PubMed

Insights

Two Pseudomonas aeruginosa genes, mpmA and mpmB, confer low susceptibility to meropenem by reducing antibiotic permeability. This discovery suggests novel meropenem translocation pathways beyond OprD2.

Area of Science:

  • Microbiology
  • Genetics
  • Pharmacology

Background:

  • Pseudomonas aeruginosa is an opportunistic pathogen known for its intrinsic and acquired resistance to antibiotics.
  • Meropenem is a critical carbapenem antibiotic used to treat serious infections caused by Gram-negative bacteria.
  • Understanding the mechanisms of meropenem resistance is crucial for developing effective treatment strategies.

Purpose of the Study:

  • To identify and characterize the genetic basis of spontaneous meropenem resistance in Pseudomonas aeruginosa.
  • To elucidate the specific mutations and their impact on antibiotic susceptibility and outer membrane protein expression.
  • To investigate potential novel pathways for meropenem translocation across the bacterial outer membrane.

Main Methods:

  • Isolation and characterization of meropenem-low-susceptibility Pseudomonas aeruginosa PAO2152 mutants.
  • Genetic mapping of resistance genes (mpmA and mpmB) on the bacterial chromosome.
  • Analysis of outer membrane protein profiles, beta-lactamase activity, and penicillin-binding protein affinities.
  • Transductional analysis to determine the allelic relationship of resistance genes.

Main Results:

  • Two distinct classes of meropenem-resistant mutants were identified, linked to mpmA and mpmB genes.
  • mpmA mutation was associated with the loss of outer membrane protein D2 (OprD2), conferring cross-resistance to carbapenems.
  • mpmB mutation increased meropenem resistance 4-fold, with cross-resistance to other agents but susceptibility to imipenem, and was linked to nalB/cfxB/oprK.
  • Both mutations appeared to reduce antibiotic permeability through the outer membrane, suggesting alternative meropenem translocation routes.

Conclusions:

  • Meropenem resistance in P. aeruginosa can arise from mutations in mpmA (linked to OprD2) and mpmB (an allele of nalB/cfxB/oprK).
  • These mutations likely reduce antibiotic permeability, indicating potential novel translocation pathways for meropenem independent of OprD2.
  • Meropenem exhibits significantly higher activity than imipenem against OprD2-deficient P. aeruginosa strains.

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