Abstract
<h3>Abstract</h3> <i>Pseudomonas aeruginosa</i> is a common opportunistic pathogen. The organism displays elevated intrinsic antibiotic resistance and can cause life-threatening infections. The gene encoding an elongation factor, FusA1, is frequently mutated in clinical isolates of <i>P. aeruginosa</i> from patients with cystic fibrosis (CF). Recent work has shown that <i>fusA1</i> mutants often display elevated aminoglycoside resistance due to increased expression of the aminoglycoside efflux pump, MexXY. In the current work, we isolated a spontaneous gentamicin-resistant <i>fusA1</i> mutant (FusA1<sup>P443L</sup>) in which <i>mexXY</i> expression was increased. Through a combination of proteomic and transcriptomic analyses, we found that the <i>fusA1</i> mutant also exhibited large-scale but discrete changes in the expression of key pathogenicity-associated genes. Most notably, the <i>fusA1</i> mutant displayed greatly increased expression of the Type III Secretion system (T3SS), widely considered to be the most potent virulence factor in the <i>P. aeruginosa</i> arsenal, and also elevated expression of the Type VI Secretion (T6S) machinery. This was unexpected because expression of the T3SS is usually reciprocally coordinated with T6S system expression. The <i>fusA1</i> mutant also displayed elevated exopolysaccharide production, dysregulated siderophore production, elevated ribosomal protein synthesis, and transcriptomic signatures indicative of translational stress. Each of these phenotypes (and almost all of the transcriptomic and proteomic changes associated with the <i>fusA1</i> mutation) were restored to levels comparable to that in the PAO1-derived progenitor strain by expression of the wild-type <i>fusA1</i> gene <i>in trans</i>, indicating that the mutant gene is recessive. Our data show that in addition to elevating antibiotic resistance through <i>mexXY</i> expression (although we also identify additional contributory resistance mechanisms), mutations in <i>fusA1</i> can lead to highly-selective dysregulation of virulence gene expression.
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