Abstract
The two-component signal transduction system CpxAR is especially widespread in Gram-negative bacteria. It has been reported that CpxAR contributes to the multidrug resistance (MDR) in Escherichia coli. CpxR is a response regulator in the two-component CpxAR system. The aim of this study was to explore the role of cpxR in the MDR of S. enterica serovar Typhimurium. The minimal inhibitory concentrations (MICs) of various antibiotics commonly used in veterinary medicine for strains JS (a multidrug-susceptible standard strain of S. enterica serovar Typhimurium), JSΔcpxR, JSΔcpxR/pcpxR, JSΔcpxR/pcpxR*, JSΔcpxRΔacrB, JSΔcpxRΔacrB/pcpxR, JSΔcpxRΔacrB/pcpxR*, 9 S. enterica serovar Typhimurium isolates (SH1–9), and SH1–9ΔcpxR were determined by the 2-fold broth microdilution method. The relative mRNA expression levels of ompF, ompC, ompW, ompD, tolC, acrB, acrD, acrF, mdtA, marA, and soxS in strains JS, JSΔcpxR, and JSΔcpxR/pcpxR were detected by real-time PCR. The results showed 2- to 4-fold decreases in the MICs of amikacin (AMK), gentamycin (GEN), apramycin (APR), neomycin (NEO), ceftriaxone (CRO), ceftiofur (CEF), and cefquinome (CEQ) for strain JSΔcpxR, as compared to those for the parental strain JS. Likewise, SH1–9ΔcpxR were found to have 2- to 8-fold reduction in resistance to the above antibiotics, except for NEO, as compared to their parental strains SH1–9. Furthermore, 2- to 4-fold further decreases in the MICs of AMK, GEN, APR, and CEF for strain JSΔcpxRΔacrB were observed, as compared to those for strain JSΔacrB. In addition, CpxR overproduction in strain JSΔcpxR led to significant decreases in the mRNA expression levels of ompF, ompC, ompW, ompD, tolC, acrB, marA, and soxS, and significant increases in those of stm3031 and stm1530. Notably, after all strains were induced simultaneously by GEN to the 15th passage at subinhibitory concentrations, strain JSΔcpxR/pcpxR showed significant increases in mRNA expression levels of the efflux pump acrD and mdtA genes, as compared to strain JSΔcpxR. Our results indicate that the two-component regulator CpxR contributes to resistance of S. enterica serovar Typhimurium to aminoglycosides and β-lactams by influencing the expression level of the MDR-related genes.
Highlights
Salmonella enterica serovar Typhimurium is a food-borne pathogen that causes gastroenteritis in humans (Scherer and Miller, 2001) and fowl typhoid in poultry (Barrow et al, 2004)
To examine whether the response regulator CpxR contributes to the drug resistance of S. enterica serovar Typhimurium, a cpxR deletion mutant, JS△cpxR, was generated from strain JS, and the complementary strain JS△cpxR/pcpxR was prepared through the introduction of the expression plasmid pBAD-CpxR into
We analyzed the effect of CpxR on the drug resistance of a susceptible strain and nine clinical isolates of S. enterica serovar Typhimurium and found 2- to 4-fold decreases in resistance to aminoglycosides and β-lactams by deletion of cpxR (Tables 3, 4)
Summary
Salmonella enterica serovar Typhimurium is a food-borne pathogen that causes gastroenteritis in humans (Scherer and Miller, 2001) and fowl typhoid in poultry (Barrow et al, 2004). In Escherichia coli, all five RND-family drug exporters confer resistance to βlactam antibiotics (Nishino et al, 2003), and acrD is known to participate in the efflux of aminoglycosides (Rosenberg et al, 2000; Nishino and Yamaguchi, 2001a; Aires and Nikaido, 2005; Nishino et al, 2007). Especially OmpF, OmpC, and OmpW, have been shown to contribute to antibiotic resistance in E. coli and Salmonella typhimurium (Nikaido, 2003). OmpD, STM3031, and STM1530 are associated with ceftriaxone (CRO) resistance in S. enterica serovar Typhimurium (Hu et al, 2011), and OmpW participates in resistance to neomycin (NEO) and ampicillin (AMP) in E. coli (Wu et al, 2012)
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