Transcriptional regulation of drug efflux genes by EvgAS, a two-component system in Escherichia coli

Eguchi, Yawara; Oshima, Taku; Mori, Hirotada; Aono, Rikizo; Yamamoto, Kaneyoshi; Ishihama, Akira; Utsumi, Ryutaro

doi:10.1099/mic.0.26460-0

Cited by 118 publications

(86 citation statements)

References 34 publications

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“…1A) and third promoters; P 2 is 8 nucleotides downstream of P 1 , and P 4 is 12 nucleotides downstream of P 3 . The leader from P 1 is 111 nucleotides, and the leader of the second fusion (P 3 ) is 53 nucleotides in length (45,46). Similar to the acrA-lacZ fusion, the tolC-lacZ fusions starting either at the P 1 or P 3 start site were very active in the absence of arabinose on the MacConkey lactose agar plates (see Fig.…”

Section: Resultsmentioning

confidence: 82%

“…The number of copies per cell of AcrB is approximately 10-to 14-fold less than that of AcrA during the log phase of growth (4), further supporting the observation of significantly lower translation activity. In E. coli, tolC is reported to have four promoters (45,46). Translational fusions were designed to begin at the start sites for the first (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Small RNA Regulation of TolC, the Outer Membrane Component of Bacterial Multidrug Transporters

Parker

Gottesman

2016

J Bacteriol

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Bacteria use multidrug efflux pumps to export drugs and toxic compounds out of the cell. One of the most important efflux pumps in Escherichia coli is the AcrAB-TolC system. Small regulatory RNAs (sRNAs) are known to be major posttranscriptional regulators that can enhance or repress translation by binding to the 5= untranslated region (UTR) of mRNA targets with the help of a chaperone protein, Hfq. In this study, we investigated the expression of acrA, acrB, and tolC translational fusions using 27 Hfq-dependent sRNAs overexpressed from plasmids. No significant sRNA regulation of acrA or acrB was detected. SdsR (also known as RyeB), an abundant and well-conserved stationary-phase sRNA, was found to repress the expression of tolC, the gene encoding the outer membrane protein of many multidrug resistance efflux pumps. This repression was shown to be by direct base pairing occurring upstream from the ribosomal binding site. SdsR overexpression and its regulation of tolC were found to reduce resistance to novobiocin and crystal violet. Our results suggest that additional targets for SdsR exist that contribute to increased antibiotic sensitivity and reduced biofilm formation. In an effort to identify phenotypes associated with single-copy SdsR and its regulation of tolC, the effect of a deletion of sdsR or mutations in tolC that should block SdsR pairing were investigated using a Biolog phenotypic microarray. However, no significant phenotypes were identified. Therefore, SdsR appears to modulate rather than act as a major regulator of its targets. IMPORTANCEAcrAB-TolC is a major efflux pump present in E. coli and Gram-negative bacteria used to export toxic compounds; the pump confers resistance to many antibiotics of unrelated classes. In this study, we found that SdsR, a small RNA expressed in stationary phase, repressed the expression of tolC, resulting in increased sensitivity to some antibiotics. This extends the findings of previous studies showing that sRNAs contribute to the regulation of many outer membrane proteins; manipulating or enhancing their action might help in sensitizing bacteria to antibiotics.

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Section: Resultsmentioning

confidence: 82%

Section: Resultsmentioning

confidence: 99%

Small RNA Regulation of TolC, the Outer Membrane Component of Bacterial Multidrug Transporters

Parker

Gottesman

2016

J Bacteriol

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“…The dosT frameshift mutation is not directly responsible for the constitutive DosR regulon overexpression phenotype. Since several previous studies have reported constitutively active mutations within sensor histidine kinases of bacterial 2CS systems (1,15,40,54), we decided to explore the possibility that the frameshift mutation in dosT results in constitutive activation of the DosR regulon for the group 2 to 5 W/Beijing strains. In order to test this, we overexpressed two distinct versions of dosT under the control of the hsp60 promoter within the H37Rv strain background.…”

Section: Vol 192 2010 M Tuberculosis Variation and Dost Sensor Kinmentioning

confidence: 99%

Strains of the East Asian (W/Beijing) Lineage ofMycobacterium tuberculosisAre DosS/DosT-DosR Two-Component Regulatory System Natural Mutants

2010

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As part of our ongoing efforts to uncover the phenotypic consequences of genetic variability among clinical Mycobacterium tuberculosis isolates, we previously reported that isolates of the "East Asian" or "W/Beijing" lineage constitutively overexpress the coordinately regulated transcriptional program known as the DosR regulon under standard in vitro conditions. This phenotype distinguishes the W/Beijing lineage from all other M. tuberculosis lineages, which normally induce expression of this regulon only once exposed to low oxygen or nitric oxide, both of which result in inhibition of bacterial respiration and replication. Transcription of the DosR regulon is controlled through a two-component regulatory system comprising the transcription factor DosR and two possible cognate histidine sensor kinases, DosS and DosT. Through sequence analysis of a carefully selected set of isolates representing each of the major M. tuberculosis lineages, we describe herein a naturally occurring frameshift mutation in the gene encoding the DosT sensor kinase for isolates of the most recently evolved W/Beijing sublineages. Intriguingly, the occurrence of the frameshift mutation correlates precisely with the appearance of the constitutive DosR regulon phenotype displayed by the same "modern" W/Beijing strains. However, complementation studies have revealed that the mutation in dosT alone is not directly responsible for the constitutive DosR regulon phenotype. Our data serve to highlight the evolutionary pressure that exists among distinct M. tuberculosis lineages to maintain tight control over DosR regulon expression.

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“…This system is associated with different pumps of RND family appearing in Gram-negative bacteria [8,25,60,81,86,94], among others AdeABC of Acinetobacter baumannii. Level of the expression of the pump, regulated by such a system, is dependent on the presence of the stimulus (substrate) in environment of the cell, which activating the pump for removing substrate outside the cell.…”

Section: Level Of Expressionmentioning

confidence: 99%

Multidrug resistant Acinetobacter baumannii--the role of AdeABC (RND family) efflux pump in resistance to antibiotics.

Wieczorek

Sacha²,

Hauschild³

et al. 2008

Folia Histochem Cytobiol.

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Abstract:Acinetobacter baumannii is an opportunistic pathogen which play the more and more greater role in the pathogenicity of the human. It is often attached with the hospital environment, in which is able easily to survive for many days even in adverse conditions. Acinetobacter baumannii is the species responsible for a serious nosocomial infections, especially in the intensive care units. Option of surviving in natural niches, and in the hospital environment could also be associated with the efflux pump mechanisms. Mechanisms of efflux universally appear in all cells (eukaryotic and prokaryotic) and play the physiological important role. In prokaryote, the main functions are evasion of such naturally produced molecules, removal of metabolic products and toxins. These pumps could also be involved in an early stage of infection, such as adhesion to host cells and the colonization. Importantly, they remove commonly used antibiotics from the cell in therapy of infections caused by these bacteria. Efflux pumps exemplify a unique phenomenon in drug resistance: a single mechanism causing resistance against several different classes of antibiotics. In Acinetobacter baumannii, the AdeABC efflux pump, a member of the resistance-nodulation-cell division family (RND), has been well characterized. Aminoglicosides, tetracyclines, erythromycin, chloramphenicol, trimethoprim, fluoroquinolones, some β-lactams, and also recently tigecycline, were found to be substrates for this pump. Drugs, as substrates for the AdeABC pump, can increase the expression of the AdeABC genes, leading to multidrug resistance (MDR). From this reason, treatment failure and death caused by Acinetobacter baumannii infections or underlying diseases are common. Because the AdeABC pump is widespread in Acinetobacter baumannii, similarly to other pumps in Gram-negative and Gram-positive bacteria, exists a need of searching a new therapeutic solutions. Specific efflux inhibitors of pumps (EPIs), including AdeABC inhibitors, could be suppress the activity of pumps and restore the sensitivity of such important bacteria as Acinetobacter baumannii to commonly used antibiotic.

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Transcriptional regulation of drug efflux genes by EvgAS, a two-component system in Escherichia coli

Cited by 118 publications

References 34 publications

Small RNA Regulation of TolC, the Outer Membrane Component of Bacterial Multidrug Transporters

Small RNA Regulation of TolC, the Outer Membrane Component of Bacterial Multidrug Transporters

Strains of the East Asian (W/Beijing) Lineage ofMycobacterium tuberculosisAre DosS/DosT-DosR Two-Component Regulatory System Natural Mutants

Multidrug resistant Acinetobacter baumannii--the role of AdeABC (RND family) efflux pump in resistance to antibiotics.

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