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Interplay of impermeability and chromosomal beta-lactamase activity in imipenem-resistant Pseudomonas aeruginosa
1Department of Medical Microbiology, London Hospital Medical College, United Kingdom.
Abstract:
Mutational loss of the D2 porin causes imipenem resistance in Pseudomonas aeruginosa. It was found that this mechanism could function only when the chromosomal beta-lactamase was expressed. Mutants lacking both the beta-lactamase and the D2 porin were almost as susceptible as those that lacked the beta-lactamase but retained the porin. Thus, imipenem resistance reflected an interplay of the enzyme and impermeability, not either factor alone. These findings suggest that the activity of a carbapenem more beta-lactamase stable than imipenem should be less affected by the porin loss. Meropenem approached this behavior.
Insights
Imipenem resistance in Pseudomonas aeruginosa arises from a combination of D2 porin loss and beta-lactamase expression. This dual mechanism highlights the interplay between bacterial impermeability and enzymatic activity for antibiotic resistance.
Area of Science:
- Microbiology
- Molecular Biology
- Antimicrobial Resistance
Background:
- Pseudomonas aeruginosa is an opportunistic pathogen known for its intrinsic and adaptive resistance mechanisms.
- Carbapenem antibiotics, like imipenem, are crucial for treating multidrug-resistant bacterial infections.
- Porins and beta-lactamases are key factors contributing to bacterial antibiotic resistance.
Purpose of the Study:
- To investigate the combined role of D2 porin mutations and chromosomal beta-lactamase expression in conferring imipenem resistance in Pseudomonas aeruginosa.
- To elucidate the interplay between bacterial impermeability and enzymatic activity in antibiotic resistance.
Main Methods:
- Analysis of Pseudomonas aeruginosa mutants with specific deficiencies in D2 porin and/or chromosomal beta-lactamase.
- Assessment of imipenem susceptibility in these distinct mutant strains.
- Comparison of resistance mechanisms involving porin loss and enzyme activity.
Main Results:
- Mutational loss of the D2 porin alone did not confer significant imipenem resistance.
- Imipenem resistance was observed only when both D2 porin loss and chromosomal beta-lactamase expression were present.
- Mutants lacking both factors were as susceptible as those lacking only the beta-lactamase, indicating a synergistic effect.
Conclusions:
- Imipenem resistance in Pseudomonas aeruginosa is a result of the combined effect of reduced drug permeability (D2 porin loss) and enzymatic degradation (beta-lactamase).
- Antibiotics with higher stability against beta-lactamases, such as meropenem, may be less affected by porin-mediated resistance mechanisms.