AUTHOR=Huang Hui , Sun Yawei , Yuan Li , Pan Yushan , Gao Yanlin , Ma Caihui , Hu Gongzheng 

TITLE=Regulation of the Two-Component Regulator CpxR on Aminoglycosides and β-lactams Resistance in Salmonella enterica serovar Typhimurium

JOURNAL=Frontiers in Microbiology

VOLUME=7

YEAR=2016

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2016.00604

DOI=10.3389/fmicb.2016.00604

ISSN=1664-302X

ABSTRACT=<p>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 <italic>Escherichia coli</italic>. CpxR is a response regulator in the two-component CpxAR system. The aim of this study was to explore the role of <italic>cpxR</italic> in the MDR of <italic>S. enterica</italic> serovar Typhimurium. The minimal inhibitory concentrations (MICs) of various antibiotics commonly used in veterinary medicine for strains JS (a multidrug-susceptible standard strain of <italic>S. enterica</italic> serovar Typhimurium), JSΔ<italic>cpxR</italic>, JSΔ<italic>cpxR</italic>/p<italic>cpxR</italic>, JSΔ<italic>cpxR</italic>/p<italic>cpxR</italic><sup>*</sup>, JSΔ<italic>cpxR</italic>Δ<italic>acrB</italic>, JSΔ<italic>cpxR</italic>Δ<italic>acrB</italic>/p<italic>cpxR</italic>, JSΔ<italic>cpxR</italic>Δ<italic>acrB</italic>/p<italic>cpxR</italic><sup>*</sup>, 9 <italic>S. enterica</italic> serovar Typhimurium isolates (SH1–9), and SH1–9Δ<italic>cpxR</italic> were determined by the 2-fold broth microdilution method. The relative mRNA expression levels of <italic>ompF, ompC, ompW, ompD, tolC, acrB, acrD, acrF, mdtA, marA</italic>, and <italic>soxS</italic> in strains JS, JSΔ<italic>cpxR</italic>, and JSΔ<italic>cpxR</italic>/p<italic>cpxR</italic> 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 JSΔ<italic>cpxR</italic>, as compared to those for the parental strain JS. Likewise, SH1–9Δ<italic>cpxR</italic> 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 JSΔ<italic>cpxR</italic>Δ<italic>acrB</italic> were observed, as compared to those for strain JSΔ<italic>acrB</italic>. In addition, CpxR overproduction in strain JSΔ<italic>cpxR</italic> led to significant decreases in the mRNA expression levels of <italic>ompF, ompC, ompW, ompD, tolC, acrB, marA</italic>, and <italic>soxS</italic>, and significant increases in those of <italic>stm3031</italic> and <italic>stm1530</italic>. Notably, after all strains were induced simultaneously by GEN to the 15th passage at subinhibitory concentrations, strain JSΔ<italic>cpxR</italic>/p<italic>cpxR</italic> showed significant increases in mRNA expression levels of the efflux pump <italic>acrD</italic> and <italic>mdtA</italic> genes, as compared to strain JSΔ<italic>cpxR</italic>. Our results indicate that the two-component regulator CpxR contributes to resistance of <italic>S. enterica</italic> serovar Typhimurium to aminoglycosides and β-lactams by influencing the expression level of the MDR-related genes.</p>