The impact of EmrA deficiency on antibiotic-susceptibility and virulence- and stone-associated phenotypes in Proteus mirabilis.

BACKGROUND

Proteus mirabilis is a common uropathogen responsible for urinary tract infections (UTIs). The emrA gene encodes the EmrA protein, which is a critical component of the EmrAB-TolC multidrug efflux pump. In addition to its established role in antibiotic resistance, emerging evidence indicates that EmrA is also implicated in bacterial stress adaptation and virulence-associated processes. Nevertheless, its specific functions in the pathogenesis of P. mirabilis remain unclear.

RESULTS

To define the function of EmrA in pathogenicity of P. mirabilis, this study combined phenotypic assays, transcriptomics, and a rat model of urinary tract infection. Comparison of the WT and ΔemrA strains showed that emrA deletion was associated with decreased MICs for carbenicillin and ampicillin, whereas the susceptibilities to most other antibiotics remained unchanged. Because MICs were not determined for the complemented strain, these results identify a deletion-associated susceptibility phenotype but do not establish an emrA-specific resistance mechanism. The study also found that EmrA promotes its adaptation to nutrient limitation, heat, and acid stress. However, the deletion of emrA significantly increased bacterial tolerance to oxidative stress. The mutant strain exhibited enhanced virulence-associated phenotypes, including increased swarming motility, biofilm formation, and improved adhesion and invasion capabilities of urothelial cells. Transcriptomic analysis revealed that emrA deletion upregulated multiple virulence-associated genes, including those encoding fimbriae components. In the rat UTI model, infection with the mutant was associated with higher bacterial burdens in the bladder and kidneys, and more severe inflammatory tissue damage; stone-associated outcomes were also increased in the models used. These stone-associated findings were accompanied by increased urease activity in the mutant strain.

CONCLUSION

This study identifies associations between emrA deletion and susceptibility changes to selected antibiotics, altered stress responses, and enhanced virulence- and stone-associated phenotypes in P. mirabilis. Because MICs were not measured for the complemented strain, the specific contribution of EmrA to the antibiotic-susceptibility phenotype remains unresolved.