Ram locus is a key regulator to trigger multidrug resistance in Enterobacter aerogenes

Molitor, A; James, CE; Fanning, S; Pages, JM; Davin-Regli, A

Abstract

Purpose: Several genetic regulators belonging to AraC family are involved in the emergence of MDR isolates of E. aerogenes due to alterations in membrane permeability. Compared with the genetic regulator Mar, RamA may be more relevant towards the emergence of antibiotic resistance.

Methodology: Focusing on the global regulators, Mar and Ram, we compared the amino acid sequences of the Ram repressor in 59 clinical isolates and laboratory strains of E. aerogenes. Sequence types were associated with their corresponding multi-drug resistance phenotypes and membrane protein expression profiles using MIC and immunoblot assays. Quantitative gene expression analysis of the different regulators and their targets (porins and efflux pump components) were performed.

Results: In the majority of the MDR isolates tested, ramR and a region upstream of ramA were mutated but marR or marA were unchanged. Expression and cloning experiments highlighted the involvement of the ram locus in the modification of membrane permeability. Overexpression of RamA lead to decreased porin production and increased expression of efflux pump components, whereas overexpression of RamR had the opposite effects.

Conclusion: Mutations or deletions in ramR, leading to the overexpression of RamA predominated in clinical MDR E. aerogenes isolates and were associated with a higher-level of expression of efflux pump components. It was hypothesised that mutations in ramR, and the self-regulating region proximal to ramA, probably altered the binding properties of the RamR repressor; thereby producing the MDR phenotype. Consequently, mutability of RamR may play a key role in predisposing E. aerogenes towards the emergence of a MDR phenotype.

Citation

Molitor, A., James, C., Fanning, S., Pages, J., & Davin-Regli, A. (2018). Ram locus is a key regulator to trigger multidrug resistance in Enterobacter aerogenes. Journal of Medical Microbiology, 67(2), 148-159. https://doi.org/10.1099/jmm.0.000667

• Journal Article Type: Article
• Acceptance Date: Dec 11, 2017
• Online Publication Date: Jan 3, 2018
• Publication Date: Jan 3, 2018
• Deposit Date: Jan 9, 2018
• Publicly Available Date: Jan 3, 2019
• Journal: Journal of Medical Microbiology
• Print ISSN: 0022-2615
• Electronic ISSN: 1473-5644
• Publisher: Microbiology Society
• Volume: 67
• Issue: 2
• Pages: 148-159
• DOI: https://doi.org/10.1099/jmm.0.000667
• Publisher URL: http://dx.doi.org/10.1099/jmm.0.000667
• Related Public URLs: http://jmm.microbiologyresearch.org/content/journal/jmm
• Additional Information: Funders : Innovative medicines Initiatives joint undertaking under grant agreement number 115525;FP7 framework programme;EEPIA companies in kind contribution;Aix-Marseille University;Service de Sante des Armees; Projects : TRANSLOCATION consortium; Grant Number: FP7/2007-2013