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Quantitative contribution of efflux to multi-drug resistance of clinical Escherichia coli and Pseudomonas aeruginosa strains

Cunrath, Olivier and Meinel, Dominik M. and Maturana, Pauline and Fanous, Joseph and Buyck, Julien M. and Saint Auguste, Pamela and Seth-Smith, Helena M. B. and Körner, Jonas and Dehio, Christoph and Trebosc, Vincent and Kemmer, Christian and Neher, Richard and Egli, Adrian and Bumann, Dirk. (2019) Quantitative contribution of efflux to multi-drug resistance of clinical Escherichia coli and Pseudomonas aeruginosa strains. EBioMedicine, 41. pp. 479-487.

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Abstract

Efflux pumps mediate antimicrobial resistance in several WHO critical priority bacterial pathogens. However, most available data come from laboratory strains. The quantitative relevance of efflux in more relevant clinical isolates remains largely unknown.; We developed a versatile method for genetic engineering in multi-drug resistant (MDR) bacteria, and used this method to delete tolC and specific antibiotic-resistance genes in 18 representative MDR clinical E. coli isolates. We determined efflux activity and minimal inhibitory concentrations for a diverse set of clinically relevant antibiotics in these mutants. We also deleted oprM in MDR P. aeruginosa strains and determined the impact on antibiotic susceptibility.; tolC deletion abolished detectable efflux activity in 15 out of 18 tested E. coli strains, and modulated antibiotic susceptibility in many strains. However, all mutant strains retained MDR status, primarily because of other, antibiotic-specific resistance genes. Deletion of oprM altered antibiotic susceptibility in a fraction of clinical P. aeruginosa isolates.; Efflux modulates antibiotic resistance in clinical MDR isolates of E. coli and P. aeruginosa. However, when other antimicrobial-resistance mechanisms are present, inhibition of MDR efflux pumps alone is often not sufficient to restore full susceptibility even for antibiotics with a dramatic impact of efflux in laboratory strains. We propose that development of novel antibiotics should include target validation in clinical MDR isolates. FUND: Innovative Medicines Initiative of European Union and EFPIA, Schweizerischer Nationalfonds, Swiss National Research Program 72, EU Marie Skłodowska-Curie program. The funders played no role in design, data collection, data analysis, interpretation, writing of the report, and in the decision to submit the paper for publication.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Computational & Systems Biology > Computational Modeling of Biological Processes (Neher)
01 Faculty of Theology > Ehemalige Organisationseinheiten Theologie > Neues Testament (Stegemann)
05 Faculty of Science > Departement Biozentrum > Infection Biology > Molecular Microbiology (Bumann)
UniBasel Contributors:Neher, Richard A and Bumann, Dirk and Dehio, Christoph
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Elsevier
e-ISSN:2352-3964
Note:Publication type according to Uni Basel Research Database: Journal article
Language:English
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Last Modified:05 Feb 2020 07:42
Deposited On:04 Nov 2019 13:59

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