Modulation of antimicrobial resistance in clinical isolates of Enterobacter aerogenes: A strategy combining antibiotics and chemosensitisers

• Published in: Journal of global antimicrobial resistance. 2019-03, Vol.16, p.187-198
• Main Authors: McCusker, Matthew P., Alves Ferreira, Daniela, Cooney, Donal, Martins Alves, Bruno, Fanning, Seámus, Pagès, Jean-Marie, Martins, Marta, Davin-Regli, Anne
• Format: Article
• Language: English
• Subjects: Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Chemical Sciences; Chemosensitisers; Combination therapy; Drug Resistance, Multiple, Bacterial; Efflux pump; Enterobacter aerogenes - drug effects; Enterobacter aerogenes - genetics; Enterobacteriaceae Infections - microbiology; Fluoroquinolones; Humans; Life Sciences; Microbial Sensitivity Tests; Multidrug resistance; Permeability
• ISSN: 2213-7165; 2213-7173
• DOI: 10.1016/j.jgar.2018.10.009

•CCCP, used as an energy poison, increases dye accumulation in resistant Enterobacter aerogenes.•Efflux inhibitors (CPZ, PAβN and NMP) restore the activity of chloramphenicol.•This approach allows an evaluation of efflux and its relevance in resistant isolates. The main focus of this study was to evaluate the antimicrobial susceptibility profiles of a number of human clinical isolates of Enterobacter aerogenes isolates and to explore the effects of selected chemosensitisers on reversal of the resistant phenotype of these isolates. This study design was accomplished by: (i) characterising several multidrug-resistant (MDR) E. aerogenes clinical isolates; (ii) evaluating the contribution of target gene mutations to the resistance phenotype, focusing on fluoroquinolones and chloramphenicol only; (iii) evaluating the contribution of membrane permeability and efflux to the MDR phenotype; (iv) assessing the combined action of selected antimicrobials and chemosensitisers in order to identify combinations with synergistic effects able to reduce the minimum inhibitory concentration (MIC); and (v) understanding how these combinations can modulate the permeability or efflux of these isolates. Resistance to ciprofloxacin could not be totally reversed owing to pre-existing mutations in target genes. Chloramphenicol susceptibility was efficiently restored by the addition of the selected chemosensitisers. From the modulation kinetics it was clear that phenothiazines were able to increase the accumulation of Hoechst dye. Modulation of permeability and efflux in the presence of chemosensitisers can help us to propose more appropriate chemotherapeutic combinations that can set the model to be used in the treatment of these and other MDR infections.