Toxic Electrophiles Induce Expression of the Multidrug Efflux Pump MexEF-OprN in Pseudomonas aeruginosa through a Novel Transcriptional Regulator, CmrA

• Published in: Antimicrobial agents and chemotherapy 2017-08, Vol.61 (8)
• Main Authors: Juarez, Paulo, Jeannot, Katy, Plésiat, Patrick, Llanes, Catherine
• Format: Article
• Language: English
• Subjects: Acrolein - analogs & derivatives; Acrolein - pharmacology; Anti-Bacterial Agents - pharmacology; AraC Transcription Factor; AraC Transcription Factor - genetics; Bacterial Outer Membrane Proteins; Bacterial Outer Membrane Proteins - biosynthesis; Bacterial Outer Membrane Proteins - genetics; Bacteriology; Chloramphenicol - pharmacology; Drug Resistance, Multiple, Bacterial; Drug Resistance, Multiple, Bacterial - genetics; Gene Expression Regulation, Bacterial; Gene Expression Regulation, Bacterial - drug effects; Glyoxal - pharmacology; Life Sciences; Mechanisms of Resistance; Membrane Transport Proteins; Membrane Transport Proteins - biosynthesis; Membrane Transport Proteins - genetics; Microbial Sensitivity Tests; Microbiology and Parasitology; Pseudomonas aeruginosa; Pseudomonas aeruginosa - drug effects; Pseudomonas aeruginosa - genetics; Pyruvaldehyde - pharmacology
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/AAC.00585-17

The multidrug efflux system MexEF-OprN is produced at low levels in wild-type strains of However, in so-called mutants, mutational alteration of the gene results in constitutive overexpression of the pump, along with increased resistance of the bacterium to chloramphenicol, fluoroquinolones, and trimethoprim. In this study, analysis of -selected chloramphenicol-resistant clones of strain PA14 led to the identification of a new class of MexEF-OprN-overproducing mutants (called ) exhibiting alterations in an as-yet-uncharacterized gene, PA14_38040 (homolog of PA2047 in strain PAO1). This gene is predicted to encode an AraC-like transcriptional regulator and was called (for hlora phenicol esistance ctivator). In mutants, the mutated CmrA increases its proper gene expression and upregulates the operon through MexS and MexT, resulting in a multidrug resistance phenotype without significant loss in bacterial virulence. Transcriptomic experiments demonstrated that CmrA positively regulates a small set of 11 genes, including PA14_38020 (homolog of PA2048), which is required for the MexS/T-dependent activation of PA2048 codes for a protein sharing conserved domains with the quinol monooxygenase YgiN from Interestingly, exposure of strain PA14 to toxic electrophilic molecules (glyoxal, methylglyoxal, and cinnamaldehyde) strongly activates the CmrA pathway and upregulates MexEF-OprN and, thus, increases the resistance of to the pump substrates. A picture emerges in which MexEF-OprN is central in the response of the pathogen to stresses affecting intracellular redox homeostasis.