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Imipenem and expression of multidrug efflux pump in Enterobacter aerogenes
Charléric Bornet1, Renaud Chollet, Monique Malléa
1Enveloppe Bactérienne, Perméabilité et Antibiotiques, EA2197, IFR48, Faculté de Médecine, Université de la Méditerranée, 27 Boulevard Jean Moulin, 13385 05, Marseille cedex, France.
Abstract:
Imipenem is often used to treat intensive care unit patients infected by Enterobacter aerogenes, but it is leading to an increasing number of antibiotic resistant strains. Clinical isolates and imipenem resistant variants presented a high level of resistance to beta-lactam antibiotic group and to chemically unrelated drugs. We report here that imipenem selects strains which contain active efflux pumps ejecting various unrelated antibiotics including quinolones, tetracycline, and chloramphenicol. An increase of AcrA, an efflux pump component, was observed in the imipenem resistant variants. The overexpression of marA, involved in the genetic control of membrane permeability via porin and efflux pump expression, indicated the activation of the resistance genetic cascade in imipenem resistant variants.
Insights
Imipenem resistance in Enterobacter aerogenes selects for strains with active efflux pumps. This leads to multi-drug resistance, driven by increased AcrA and MarA expression, impacting antibiotic treatment efficacy.
Area of Science:
- Microbiology
- Molecular Biology
- Pharmacology
Background:
- Imipenem is a crucial antibiotic for treating Enterobacter aerogenes infections in intensive care units.
- Increasing antibiotic resistance, particularly to beta-lactam drugs, poses a significant clinical challenge.
- Enterobacter aerogenes is a common nosocomial pathogen, and resistance mechanisms are of growing concern.
Purpose of the Study:
- To investigate the mechanisms by which imipenem resistance emerges in Enterobacter aerogenes.
- To identify genetic factors and cellular processes associated with imipenem resistance and multi-drug resistance.
- To understand how imipenem treatment selects for resistant strains with altered drug efflux capabilities.
Main Methods:
- Comparative analysis of imipenem-susceptible and imipenem-resistant clinical isolates of Enterobacter aerogenes.
- Phenotypic characterization of antibiotic resistance profiles, including susceptibility testing to various drug classes.
- Molecular techniques to assess the expression levels of efflux pump components (e.g., AcrA) and regulatory genes (e.g., MarA).
Main Results:
- Imipenem-resistant Enterobacter aerogenes strains exhibited cross-resistance to chemically unrelated antibiotics, including quinolones, tetracycline, and chloramphenicol.
- A significant increase in the expression of AcrA, a key component of the AcrAB-TolC efflux pump, was observed in resistant variants.
- Overexpression of the marA gene was detected, indicating the activation of a genetic cascade controlling membrane permeability and efflux pump activity.
Conclusions:
- Imipenem treatment selects for Enterobacter aerogenes strains possessing active efflux pumps, leading to multi-drug resistance.
- The upregulation of AcrA and MarA plays a critical role in the development of imipenem resistance and associated efflux-mediated drug extrusion.
- Understanding these resistance mechanisms is vital for developing effective therapeutic strategies against resistant Enterobacter aerogenes infections.