Role of Mutations in the Resistance to Aminoglycosides and β-Lactams in serovar Typhimurium.

Although it has been reported that deletion of the response regulator, CpxR, in the CpxRA system confers sensitivity to aminoglycosides (AGAs) and β-lactams in serovar Typhimurium, the regulatory effects of CpxA on multidrug resistance (MDR) are yet to be fully investigated in this organism. Here, to explore the role of CpxA in MDR, various mutants including a null mutant (JSΔ), a site-directed mutant (JSΔ ) and an internal in-frame deletion mutant (JSΔ ) of the serovar Typhimurium strain JS, were constructed. It was revealed that and deletion mutants have opposing roles in the regulation of resistance to AGAs and β-lactams. Amikacin and cefuroxime can activate the CpxRA system, which results in increased resistance of the wild-type compared with the deletion mutant. All the mutations significantly increased resistance to AGAs and β-lactams due to CpxRA system activation the phosphorylation of CpxR. Moreover, AckA-Pta-dependent activation of CpxR increased the antibiotic resistance of deletion mutants. Further research revealed that the AcrAB-TolC conferred resistance to some AGAs and β-lactams but does not influence the regulation of resistance by CpxRA against these antibiotics. The detection of candidate MDR-related CpxR regulons revealed that the mRNA expression levels of , , , , , and were upregulated and that of was downregulated in various mutants. Furthermore, the expression levels of and mRNAs were downregulated only in JSΔ . These results suggested that mutations contribute to AGAs and β-lactams resistance, which is dependent on CpxR.