Global reprogramming of virulence and antibiotic resistance in by a single nucleotide polymorphism in elongation factor, .

Clinical isolates of the opportunistic pathogen from patients with cystic fibrosis (CF) frequently contain mutations in the gene encoding an elongation factor, FusA1. Recent work has shown that mutants often display elevated aminoglycoside resistance due to increased expression of the efflux pump, MexXY. However, we wondered whether these mutants might also be affected in other virulence-associated phenotypes. Here, we isolated a spontaneous gentamicin-resistant mutant (FusA1) in which expression was increased. Proteomic and transcriptomic analyses revealed that the mutant also exhibited discrete changes in the expression of key pathogenicity-associated genes. Most notably, the mutant displayed greatly increased expression of the Type III secretion system (T3SS), widely considered to be the most potent virulence factor in the arsenal, and also elevated expression of the Type VI (T6) secretion machinery. This was unexpected because expression of the T3SS is usually reciprocally coordinated with T6 secretion system expression. The mutant also displayed elevated exopolysaccharide production, dysregulated siderophore production, elevated ribosome synthesis, and transcriptomic signatures indicative of translational stress. Each of these phenotypes (and almost all of the transcriptomic and proteomic changes associated with the mutation) were restored to levels comparable with that in the progenitor strain by expression of the WT gene in , indicating that the mutant gene is recessive. Our data show that in addition to elevating antibiotic resistance through expression (and also additional contributory resistance mechanisms), mutations in can lead to highly selective dysregulation of virulence gene expression.