Abstract
The impact of MexXY efflux pump expression on aminoglycoside resistance in clinical Pseudomonas aeruginosa isolates has been debated. In this study, we found that, in general, elevated mexXY gene expression levels in clinical P. aeruginosa isolates confer to slight increases in aminoglycoside MIC levels; however, those levels rarely lead to clinically relevant resistance phenotypes. The main driver of resistance in the clinical isolates studied here was the acquisition of aminoglycoside-modifying enzymes (AMEs). Nevertheless, acquisition of an AME was strongly associated with mexY overexpression. In line with this observation, we demonstrate that the introduction of a gentamicin acetyltransferase confers to full gentamicin resistance levels in a P. aeruginosa type strain only if the MexXY efflux pump was active. We discuss that increased mexXY activity in clinical AME-harboring P. aeruginosa isolates might affect ion fluxes at the bacterial cell membrane and thus might play a role in the establishment of enhanced fitness that extends beyond aminoglycoside resistance.
Highlights
We found that clinically relevant tobramycin resistance was in general not associated with elevated mexXY gene expression levels, but that the acquisition of aminoglycoside modifying enzymes (AMEs) was the main driver of resistance
Aminoglycosides remain important in the treatment of P. aeruginosa infections, despite their known toxicity
In cystic fibrosis (CF) for example, tobramycin inhalation is applied as a means to control chronic infection, and as a first-line treatment for the eradication of early acquisition of P. aeruginosa
Summary
Expression of the MexXY aminoglycoside efflux pump and presence of an aminoglycoside modifying enzyme in clinical Pseudomonas aeruginosa isolates are highly correlated. We found that in general, elevated mexXY gene expression levels in clinical P. aeruginosa isolates confer to slight increases in aminoglycoside MIC levels, those levels rarely lead to clinically relevant resistance phenotypes. The main driver of resistance in the clinical isolates studied here was the acquisition of aminoglycoside modifying enzymes (AMEs). In line with this observation, we demonstrate that the introduction of a gentamicin acetyltransferase confers to full gentamicin resistance levels in a P. aeruginosa type strain only if the MexXY efflux pump was active. AME harboring P. aeruginosa isolates might affect ion fluxes at the bacterial cell membrane and might play a role in the establishment of enhanced fitness that extends beyond aminoglycoside resistance
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