AUTHOR=Jing Wenxian , Liu Juan , Wu Shanshan , Li Xuerui , Liu Yongsheng 

TITLE=Role of cpxA Mutations in the Resistance to Aminoglycosides and β-Lactams in Salmonella enterica serovar Typhimurium

JOURNAL=Frontiers in Microbiology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2021.604079

DOI=10.3389/fmicb.2021.604079

ISSN=1664-302X

ABSTRACT=<p>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 <italic>Salmonella enterica</italic> 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 <italic>cpxA</italic> mutants including a null mutant (JSΔ<italic>cpxA</italic>), a site-directed mutant (JSΔ<italic>cpxA</italic><sub>38</sub>) and an internal in-frame deletion mutant (JSΔ<italic>cpxA<sub>92</sub><sub>–</sub><sub>104</sub></italic>) of the <italic>S. enterica</italic> serovar Typhimurium strain JS, were constructed. It was revealed that <italic>cpxA</italic> and <italic>cpxR</italic> 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 <italic>cpxR</italic> deletion mutant. All the <italic>cpxA</italic> mutations significantly increased resistance to AGAs and β-lactams due to CpxRA system activation <italic>via</italic> the phosphorylation of CpxR. Moreover, AckA-Pta-dependent activation of CpxR increased the antibiotic resistance of <italic>cpxA</italic> 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 <italic>spy</italic>, <italic>ycca</italic>, <italic>ppia</italic>, <italic>htpX</italic>, <italic>stm3031</italic>, and <italic>acrD</italic> were upregulated and that of <italic>ompW</italic> was downregulated in various <italic>cpxA</italic> mutants. Furthermore, the expression levels of <italic>nuoA</italic> and <italic>sdhC</italic> mRNAs were downregulated only in JSΔ<italic>cpxA<sub>92</sub><sub>–</sub><sub>104</sub></italic>. These results suggested that <italic>cpxA</italic> mutations contribute to AGAs and β-lactams resistance, which is dependent on CpxR.</p>