RNAIII of the
            <i>Staphylococcus aureus agr</i>
            system activates global regulator MgrA by stabilizing mRNA

Gupta, Ravi; Luong, Thanh T.; Lee, Chia Y.

doi:10.1073/pnas.1509251112

Cited by 83 publications

(68 citation statements)

References 49 publications

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“…However, deletion of the entire Agr locus resulted in a significant increase in abundance FBP and EbhB which is consistent with Agr‐mediated repression at this time point in in vitro culture. The limited upregulation of these proteins in the Rot deletion (except for FnBP) suggests there is potentially another factor that is repressing the expression of these proteins, with MgrA the most likely candidate (Gupta et al , ). Comparatively, ClfA appeared to be positively regulated by Rot, and the RNAIII complement restored protein abundance almost to wild‐type levels, suggesting this protein is regulated by the Agr/Rot axis but the opposite to TSST‐1.…”

Section: Discussionmentioning

confidence: 99%

Regulation of toxic shock syndrome toxin‐1 by the accessory gene regulator in Staphylococcus aureus is mediated by the repressor of toxins

Tuffs

Herfst

Baroja

et al. 2019

Molecular Microbiology

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Summary Toxic shock syndrome toxin‐1 (TSST‐1) is a superantigen (SAg) produced by Staphylococcus aureus thought to be responsible for essentially all cases of menstrual‐associated toxic shock syndrome (TSS). As a potent exotoxin, it is not surprising that S. aureus has evolved multiple systems to control expression of TSST‐1. Although the accessory gene regulator (Agr) system is recognized to enhance TSST‐1 expression, how Agr regulates TSST‐1 is unclear. Using an agr‐null mutant, complementation experiments demonstrated that Agr controls TSST‐1 expression through the activity of the RNAIII effector molecule. RNAIII can repress translation of the repressor of toxins (Rot) regulator, and deletion of rot increased expression of TSST‐1 during the exponential phase of growth. Deletion of agr did not affect rot transcription, but did result in overexpression of the Rot protein, and Rot was also shown to bind and positively regulate the rot promoter. Overexpression of Rot dramatically repressed TSST‐1, and Rot bound directly to the TSST‐1 promoter. Deletion of both agr and rot in S. aureus returned TSST‐1 expression to wild‐type levels. This work demonstrates that Agr, although widely considered to be an inducer of TSST‐1, has evolved in combination with Rot, to restrict the expression of this potent SAg.

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Section: Discussionmentioning

confidence: 99%

Regulation of toxic shock syndrome toxin‐1 by the accessory gene regulator in Staphylococcus aureus is mediated by the repressor of toxins

Tuffs

Herfst

Baroja

et al. 2019

Molecular Microbiology

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“…[266] Activation rather than inhibition of ClpP by natural products called acyldepsipeptides (ADEPs) led to killing of the cell by uncontrolled degradation of essential proteins. [269,270] Thus,i ti sa ni ntriguing antivirulence target. [268] Tr anscriptional regulation represents another central mechanism which directly affects the expression of virulence genes.Here,the global transcriptional regulator A(MgrA) of the MarR family regulates more than 350 genes in S. aureus related to,f or example,v irulence,c lumping,a nd antibiotic resistance.…”

Section: Clpp Clpx Mgra and Toxt Modulatorsmentioning

confidence: 99%

Thinking Outside the Box—Novel Antibacterials To Tackle the Resistance Crisis

et al. 2018

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The public view on antibiotics as reliable medicines changed when reports about "resistant superbugs" appeared in the news. While reasons for this resistance development are easily spotted, solutions for re-establishing effective antibiotics are still in their infancy. This Review encompasses several aspects of the antibiotic development pipeline from very early strategies to mature drugs. An interdisciplinary overview is given of methods suitable for mining novel antibiotics and strategies discussed to unravel their modes of action. Select examples of antibiotics recently identified by using these platforms not only illustrate the efficiency of these measures, but also highlight promising clinical candidates with therapeutic potential. Furthermore, the concept of molecules that disarm pathogens by addressing gatekeepers of virulence will be covered. The Review concludes with an evaluation of antibacterials currently in clinical development. Overall, this Review aims to connect select innovative antimicrobial approaches to stimulate interdisciplinary partnerships between chemists from academia and industry.

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“…AgrA also directly represses the expression of ArtR sRNA (29), termed ‘Srn_4050’ in SRD. Conversely, RNAIII and ArtR negatively regulate the Rot and SarT TFs, respectively (4,30,31), and RNAIII stabilizes mgrA mRNA thereby increasing MgrA TF production (32). Since TFs have numerous targets, sRNA regulation of TF expression allows sRNAs to play an important role in adaptation.…”

Section: Introductionmentioning

confidence: 99%

Insights into the regulation of small RNA expression: SarA represses the expression of two sRNAs inStaphylococcus aureus

Mauro¹,

Rouillon²,

Felden³

2016

Nucleic Acids Res

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The opportunistic pathogen Staphylococcus aureus expresses transcription factors (TFs) and regulatory small RNAs (sRNAs) which are essential for bacterial adaptation and infectivity. Until recently, the study of S. aureus sRNA gene expression regulation was under investigated, but it is now an expanding field. Here we address the regulation of Srn_3610_SprC sRNA, an attenuator of S. aureus virulence. We demonstrate that SarA TF represses srn_3610_sprC transcription. DNase I footprinting and deletion analyses show that the SarA binding site on srn_3610_sprC belongs to an essential 22 bp DNA region. Comparative analysis also revealed another possible site, this time in the srn_9340 promoter. SarA specifically binds these two sRNA promoters with high affinity in vitro and also represses their transcription in vivo. Chromatin immunoprecipitation (ChIP) assays confirmed SarA attachment to both promoters. ChIP and electrophoretic mobility shift assays targeting σA RNA polymerase subunit or using bacterial RNA polymerase holoenzyme suggested that SarA and the σA bind srn_3610_sprC and srn_9340 promoters in a mutually exclusive way. Beyond the mechanistic study of SarA repression of these two sRNAs, this work also suggests that some S. aureus sRNAs belong to the same regulon and act jointly in responding to environmental changes.

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RNAIII of the Staphylococcus aureus agr system activates global regulator MgrA by stabilizing mRNA

Cited by 83 publications

References 49 publications

Regulation of toxic shock syndrome toxin‐1 by the accessory gene regulator in Staphylococcus aureus is mediated by the repressor of toxins

Regulation of toxic shock syndrome toxin‐1 by the accessory gene regulator in Staphylococcus aureus is mediated by the repressor of toxins

Thinking Outside the Box—Novel Antibacterials To Tackle the Resistance Crisis

Insights into the regulation of small RNA expression: SarA represses the expression of two sRNAs inStaphylococcus aureus

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