Complex Response of the CpxAR Two-Component System to β-Lactams on Antibiotic Resistance and Envelope Homeostasis in
            <i>Enterobacteriaceae</i>

Masi, Muriel; Pinet, Elizabeth; Pagès, Jean‐Marie

doi:10.1128/aac.00291-20

Cited by 35 publications

(26 citation statements)

References 69 publications

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“…The CpxRA envelope stress response system is closely related to drug resistance. In E. coli , cpxA deletion or cpxA ∗ mutations will confer the resistance to hydroxyurea, β-lactams, aminoglycosides, and fosfomycin ( Mahoney and Silhavy, 2013 ; Masi et al, 2020 ). Moreover, overexpression of cpxR can confer the resistance to kanamycin, amikacin, deoxycholate, novobiocin, and β-lactams ( Hirakawa et al, 2003a , b ).…”

Section: Introductionmentioning

confidence: 99%

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

Jing

Liu

et al. 2021

Front. Microbiol.

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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 Salmonella enterica 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 cpxA mutants including a null mutant (JSΔcpxA), a site-directed mutant (JSΔcpxA38) and an internal in-frame deletion mutant (JSΔcpxA92–104) of the S. enterica serovar Typhimurium strain JS, were constructed. It was revealed that cpxA and cpxR 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 cpxR deletion mutant. All the cpxA mutations significantly increased resistance to AGAs and β-lactams due to CpxRA system activation via the phosphorylation of CpxR. Moreover, AckA-Pta-dependent activation of CpxR increased the antibiotic resistance of cpxA 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 spy, ycca, ppia, htpX, stm3031, and acrD were upregulated and that of ompW was downregulated in various cpxA mutants. Furthermore, the expression levels of nuoA and sdhC mRNAs were downregulated only in JSΔcpxA92–104. These results suggested that cpxA mutations contribute to AGAs and β-lactams resistance, which is dependent on CpxR.

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Section: Introductionmentioning

confidence: 99%

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

Jing

Liu

et al. 2021

Front. Microbiol.

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“…These other mutations were nonetheless never detected at frequency higher than 5% in any of the sequenced populations (supplementary Table S3). Moderate MIC increase (20 to 24 µg/mL) in evolved planktonic clones were associated with mutations in sbmA, or in cpxA , the histidine kinase component of the cpx system known to be associated with increase resistance to aminoglycosides through regulation of the expression of porins and efflux pumps (Masi et al , 2020). Mutations associated with higher MICs corresponded, in combination or not with sbmA alleles, to mutations in genes linked to aminoglycosides resistance via their capacity to modulate the proton motive force (PMF), notably genes encoding components of the Ubi complex responsible for the biosynthesis of ubiquinone ( ubiF, ubiH, ubiI, ubiJ ) (Aussel et al , 2014; Muir et al , 1981; Xia et al , 2017) or genes belonging to NADH-quinone oxidoreductase Nuo ( nuoF , nuoG ) (El’Garch et al , 2007; Wistrand-Yuen et al , 2018).…”

Section: Resultsmentioning

confidence: 99%

Intermittent antibiotic treatment of bacterial biofilms favors the rapid evolution of resistance

Usui

Yoshii

Thiriet-Rupert

et al. 2022

Preprint

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The rise of antibiotic resistance in bacterial pathogens is a major health concern and the determinants of this emergence are actively studied. By contrast, although biofilms are an important cause of infections due to their high tolerance to a broad range of antimicrobials, much less is known on the development of antibiotic resistance within the biofilm environment, an issue potentially aggravating the current antibiotic crisis. Here, we compared the occurrence of resistance mutations in pathogenic Escherichia coli planktonic and biofilm populations exposed to clinically relevant cycles of lethal treatments with the aminoglycoside antibiotic amikacin. This experimental evolution approach revealed that mutations in sbmA and fusA are rapidly selected in biofilm but not in planktonic populations. The apparition of these bona fide resistance (and not tolerance) mutations is favored by the biofilm preexisting tolerance and high mutation rate. Moreover, we showed that while fusA mutations displayed a high fitness cost in planktonic conditions, these mutations were maintained in biofilms, a phenomenon further possibly amplified by the selection of fimH mutations favoring biofilm formation itself. Our study therefore provides new insights into the dynamic evolution of antibiotic resistance in biofilms, which could lead to clinically practical antibiotic regimen limiting biofilm-associated infections, while mitigating the emergence of worrisome antibiotic resistance mutations.

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“…Moreover, the lower activity of the SoxS and MarA regulators and decrease in acrB expression was observed, which suggest that CpxR can decrease acrB expression via SoxS and MarA regulation [ 11 ]. Another study [ 128 ] confirmed that antibiotic resistance is acquired in a CpxR-dependent manner through regulation of the OmpF porin and of the AcrD efflux pump. The AcrAB efflux pump contains an outer membrane protein (TolC), cooperating with many transporters, such as AcrD and MdtABC, to remove drugs from pathogen cells [ 129 ].…”

Section: Molecular Systems Of Multiple Resistance In Salmonellamentioning

confidence: 93%

Transcriptional Regulation of the Multiple Resistance Mechanisms in Salmonella—A Review

et al. 2021

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The widespread use of antibiotics, especially those with a broad spectrum of activity, has resulted in the development of multidrug resistance in many strains of bacteria, including Salmonella. Salmonella is among the most prevalent causes of intoxication due to the consumption of contaminated food and water. Salmonellosis caused by this pathogen is pharmacologically treated using antibiotics such as fluoroquinolones, ceftriaxone, and azithromycin. This foodborne pathogen developed several molecular mechanisms of resistance both on the level of global and local transcription modulators. The increasing rate of antibiotic resistance in Salmonella poses a significant global concern, and an improved understanding of the multidrug resistance mechanisms in Salmonella is essential for choosing the suitable antibiotic for the treatment of infections. In this review, we summarized the current knowledge of molecular mechanisms that control gene expression related to antibiotic resistance of Salmonella strains. We characterized regulators acting as transcription activators and repressors, as well as two-component signal transduction systems. We also discuss the background of the molecular mechanisms of the resistance to metals, regulators of multidrug resistance to antibiotics, global regulators of the LysR family, as well as regulators of histone-like proteins.

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Complex Response of the CpxAR Two-Component System to β-Lactams on Antibiotic Resistance and Envelope Homeostasis in Enterobacteriaceae

Cited by 35 publications

References 69 publications

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

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

Intermittent antibiotic treatment of bacterial biofilms favors the rapid evolution of resistance

Transcriptional Regulation of the Multiple Resistance Mechanisms in Salmonella—A Review

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