The role of AxyZ transcriptional regulator in the overproduction of AxyXY-OprZ multidrug efflux system in Achromobacter spp. mutants selected by tobramycin. [PublishAheadOfPrint]

AxyXY-OprZ is an RND-type efflux system that confers innate aminoglycoside resistance to Achromobacter spp. We investigated here about a putative TetR family transcriptional regulator encoded by the axyZ gene located upstream of axyXY-oprZ. In-frame axyZ gene deletion assay led to increased MICs of antibiotic substrates of the efflux system: aminoglycosides, cefepime, fluoroquinolones, tetracyclines and erythromycin, indicating that the product of axyZ negatively regulates expression of axyXY-oprZ. Moreover we identified an amino-acid substitution at position 29 of AxyZ (V29G) in a clinical Achromobacter strain that occurred during the course of chronic respiratory tract colonization in a cystic fibrosis (CF) patient. This substitution, also detected in 3 other strains exposed in vitro to tobramycin, led to the increase in axyY transcription level (5 to 17-fold) together with the increase in antibiotic resistance level. This overproduction of AxyXY-OprZ is the first description of antibiotic resistance acquisition due to modification of a chromosomally encoded mechanism in Achromobacter and might have potential impact on the management of infected CF patients. Indeed tobramycin is widely used for aerosol therapy within this population and we have demonstrated that it easily selects mutants with increased minimal inhibitory concentrations of aminoglycosides but also fluoroquinolones, cefepime and tetracyclines.

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