Effects of Natural Mutations in the ramRA Locus on Invasiveness of Epidemic Fluoroquinolone-Resistant Salmonella enterica Serovar Typhimurium Isolates

• Published in: The Journal of infectious diseases 2013-03, Vol.207 (5), p.794-802
• Main Authors: Giraud, Etienne, Baucheron, Sylvie, Virlogeux-Payant, Isabelle, Nishino, Kunihiko, Cloeckaert, Axel
• Format: Article
• Language: English
• Subjects: Antimicrobials; Bacteria; Bacterial Proteins - genetics; Bacterial Proteins - metabolism; Bacteriology; Biological and medical sciences; Drug Resistance, Bacterial; Epidemics; Epithelial cells; Epithelial Cells - microbiology; Fluoroquinolones - pharmacology; Fundamental and applied biological sciences. Psychology; Gene Expression Profiling; Genes; Genetic mutation; HT29 cells; Humans; Infectious diseases; Life Sciences; MAJOR ARTICLES AND BRIEF REPORTS; Medical sciences; Microbiology; Microbiology and Parasitology; Miscellaneous; Multidrug Resistance-Associated Proteins - genetics; Multidrug Resistance-Associated Proteins - metabolism; Mutant Proteins - genetics; Mutant Proteins - metabolism; Mutation; Real-Time Polymerase Chain Reaction; Repressor Proteins - genetics; Repressor Proteins - metabolism; Resistance mechanisms; Salmonella; Salmonella enterica; Salmonella Infections - epidemiology; Salmonella Infections - microbiology; Salmonella typhimurium - drug effects; Salmonella typhimurium - genetics; Salmonella typhimurium - isolation & purification; Salmonella typhimurium - pathogenicity; Trans-Activators - genetics; Trans-Activators - metabolism; Virulence; Virulence Factors - genetics; Virulence Factors - metabolism
• ISSN: 0022-1899; 1537-6613
• DOI: 10.1093/infdis/jis755

Background. Fluoroquinolone (FQ) resistance is increasing worldwide among Salmonella species. Among the mechanisms involved, increased efflux via the tripartite AcrAB-TolC efflux system is mainly modulated through control of expression via the ramRA regulatory locus gene products. Interestingly, in some reference strains these have also been experimentally shown to regulate cell invasion—related genes of the type III secretion system 1 (T3SS-1). In this study, we investigated whether natural mutations occurring in this locus in FQ-resistant S. enterica serovar Typhimurium epidemic clones resulted in the same effects. Methods. Quantitative reverse transcription polymerase chain reaction and cell invasion assays were used to study 3 clinical FQ-resistant S. Typhimurium isolates representative of the DT104 and DT204 epidemic clones. For comparison, 3 control reference quinolone-susceptible strains were included. Results. As previously shown, the investigated mutations altering RamR or its DNA-binding site increased expression of efflux genes dependently on ramA. However, the decreased expression of T3SS-1 genes previously reported was not always observed and seemed to be dependent on the genetic background of the FQ-resistant isolate. Indeed, a ramA-dependent decreased invasion of intestinal epithelial cells was only observed for a particular clinical ramR mutant. Conclusions. ramRA mutations occurring in clinical FQ-resistant S. Typhimurium isolates may negatively modulate their invasiveness but this is strain-dependent.