Efflux-mediated antibiotic resistance in Acinetobacter spp
Sébastien Coyne1, Patrice Courvalin, Bruno Périchon
1Institut Pasteur, Unité des Agents Antibactériens, 28 Rue du Docteur Roux, 75724 Paris Cedex 15, France.
Abstract:
Among Acinetobacter spp., A. baumannii is the most frequently implicated in nosocomial infections, in particular in intensive care units. It was initially thought that multidrug resistance (MDR) in this species was due mainly to horizontal acquisition of resistance genes. However, it has recently become obvious that increased expression of chromosomal genes for efflux systems plays a major role in MDR. Among the five superfamilies of pumps, resistance-nodulation-division (RND) systems are the most prevalent in multiply resistant A. baumannii. RND pumps typically exhibit a wide substrate range that can include antibiotics, dyes, biocides, detergents, and antiseptics. Overexpression of AdeABC, secondary to mutations in the adeRS genes encoding a two-component regulatory system, constitutes a major mechanism of multiresistance in A. baumannii. AdeIJK, intrinsic to this species, is responsible for natural resistance, but since overexpression above a certain threshold is toxic for the host, its contribution to acquired resistance is minimal. The recently described AdeFGH, probably regulated by a LysR-type transcriptional regulator, also confers multidrug resistance when overexpressed. Non-RND efflux systems, such as CraA, AmvA, AbeM, and AbeS, have also been characterized for A. baumannii, as have AdeXYZ and AdeDE for other Acinetobacter spp. Finally, acquired narrow-spectrum efflux pumps, such as the major facilitator superfamily (MFS) members TetA, TetB, CmlA, and FloR and the small multidrug resistance (SMR) member QacE in Acinetobacter spp., have been detected and are mainly encoded by mobile genetic elements.
Insights
Multidrug resistance in Acinetobacter baumannii is significantly driven by increased expression of chromosomal efflux pumps, particularly resistance-nodulation-division (RND) systems, rather than solely gene acquisition.
Area of Science:
- Microbiology
- Molecular Biology
- Genetics
Background:
- Acinetobacter baumannii is a major cause of nosocomial infections, especially in intensive care units.
- Multidrug resistance (MDR) in A. baumannii was previously attributed mainly to acquired resistance genes.
- Emerging evidence highlights the critical role of increased expression of chromosomal efflux systems in MDR.
Purpose of the Study:
- To investigate the role of efflux pump gene expression in multidrug resistance in Acinetobacter baumannii.
- To identify the prevalent efflux pump systems contributing to MDR in this opportunistic pathogen.
Main Methods:
- Analysis of gene expression levels of various efflux pump systems.
- Identification of mutations in regulatory genes associated with efflux pump overexpression.
- Characterization of the substrate range and contribution of different efflux pumps to resistance.
Main Results:
- Resistance-nodulation-division (RND) systems are the most prevalent pumps in multiply resistant A. baumannii.
- Overexpression of the AdeABC system, due to mutations in adeRS, is a primary MDR mechanism.
- Other RND (AdeFGH), non-RND (CraA, AmvA, AbeM, AbeS), and acquired efflux pumps (MFS, SMR) also contribute to resistance.
Conclusions:
- Increased expression of chromosomal efflux systems, especially RND pumps like AdeABC, is a key driver of MDR in A. baumannii.
- While intrinsic pumps like AdeIJK contribute to natural resistance, their overexpression is limited by toxicity.
- Understanding these efflux mechanisms is crucial for developing strategies to combat MDR infections caused by A. baumannii.
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