Role of global regulator Rma for multidrug efflux-mediated fluoroquinolone resistance in Salmonella.
The genetic basis for multidrug resistance (mdr) due to overexpression of mdr efflux pumps in Escherichia coli usually includes alterations in genes encoding global regulators, like MarA, SoxS, and Rob. In Salmonella, in addition to these regulators, Rma, for which no homolog exists in E. coli, seems to play a role in the regulation of efflux pumps. However, the exact mechanisms remain unclear. Therefore, this study aimed at investigating the influence of the regulator Rma on the expression of mdr efflux pumps in Salmonella Hadar by overexpression of the potential activator. Overexpression of rma (about 80-fold) from a plasmid led to an increase in the minimum inhibitory concentrations (MICs) of (fluoro)quinolones (2-4-fold), chloramphenicol (3-fold), tetracycline (4-fold), and novobiocin (3-fold), which is associated with an elevated expression of the mdr efflux pumps AcrAB-TolC, AcrEF-TolC, and MdtABC (formerly known as YegMNO)-TolC (all about 15-fold) as has been demonstrated by quantitative real-time PCR experiments. To assess a putative general relevance of Rma for fluoroquinolone resistance, clinical isolates of Salmonella Typhimurium DT104 and DT204c and Salmonella Hadar, which showed elevated MICs, were investigated concerning rma and acrA gene expression levels. All clinical isolates showed an elevated expression of rma (up to 16-fold) and acrA (up to 3-fold) compared to the respective wild-type strains. Thus, the global regulator Rma is important in Salmonella concerning elevated expression of several mdr efflux pumps and hence resulting increase in antibiotic resistance.
Feuerriegel
Silke
S
Pharmaceutical Biology and Microbiology, University of Hamburg, Bundesstrasse, Hamburg, Germany. sfeuerriegel@fz-borstel.de
Heisig
Peter
P
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D024901:Drug Resistance, Multiple, Bacterial / Q000235:genetics*; D024841:Fluoroquinolones / Q000494:pharmacology*; D015964:Gene Expression Regulation, Bacterial; D006801:Humans; D008826:Microbial Sensitivity Tests; D010957:Plasmids / Q000235:genetics; D012480:Salmonella Infections / Q000382:microbiology; D019779:Salmonella enterica / Q000145:classification / Q000187:drug effects* / Q000235:genetics; D012486:Salmonella typhimurium / Q000187:drug effects* / Q000235:genetics; D015854:Up-Regulation
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D024841:Fluoroquinolones; C453342:rma protein, Salmonella