MgrA Negatively Regulates Biofilm Formation and Detachment by Repressing the Expression of
            <i>psm</i>
            Operons in Staphylococcus aureus

Jiang, Qiu Xing; Jin, Zeyu; Sun, Baolin

doi:10.1128/aem.01008-18

Cited by 40 publications

(33 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, (pp)pGpp-mediated psm activation is clearly uncoupled from agr expression. Recently, the sRNA Teg41 (S131) [ 59 ] and the transcriptional regulator MgrA [ 60 ], Rsp [ 61 ] or Rbf [ 62 ] were found to interfere with psm expression. However, it is unlikely that they mediate the (pp)pGpp regulatory effect because transcription of these regulators was unaltered based on our RNA-Seq analysis ( S1 Data ).…”

Section: Discussionmentioning

confidence: 99%

Inducible expression of (pp)pGpp synthetases in Staphylococcus aureus is associated with activation of stress response genes

et al. 2020

View full text Add to dashboard Cite

The stringent response is characterized by the synthesis of the messenger molecules pppGpp, ppGpp or pGpp (here collectively designated (pp)pGpp). The phenotypic consequences resulting from (pp)pGpp accumulation vary among species and can be mediated by different underlying mechanisms. Most genome-wide analyses have been performed under stress conditions, which often mask the immediate effects of (pp)pGpp-mediated regulatory circuits. In Staphylococcus aureus, (pp)pGpp can be synthesized via the RelA-SpoT-homolog, RelSau upon amino acid limitation or via one of the two small (pp)pGpp synthetases RelP or RelQ upon cell wall stress. We used RNA-Seq to compare the global effects in response to induction of the synthetase of rel-Syn (coding for the enzymatic region of RelSau) or relQ without the need to apply additional stress conditions. Induction of rel-Syn resulted in changes in the nucleotide pool similar to induction of the stringent response via the tRNA synthetase inhibitor mupirocin: a reduction in the GTP pool, an increase in the ATP pool and synthesis of pppGpp, ppGpp and pGpp. Induction of all three enzymes resulted in similar changes in the transcriptome. However, RelQ was less active than Rel-Syn and RelP, indicating strong restriction of its (pp)pGpp-synthesis activity in vivo. (pp)pGpp induction resulted in the downregulation of many genes involved in protein and RNA/DNA metabolism. Many of the (pp)pGpp upregulated genes are part of the GTP sensitive CodY regulon and thus likely regulated through lowering of the GTP pool. New CodY independent transcriptional changes were detected including genes involved in the SOS response, iron storage (e.g. ftnA, dps), oxidative stress response (e.g., perR, katA, sodA) and the psmα1–4 and psmß1-2 operons coding for cytotoxic, phenol soluble modulins (PSMs). Analyses of the ftnA, dps and psm genes in different regulatory mutants revealed that their (pp)pGpp-dependent regulation can occur independent of the regulators PerR, Fur, SarA or CodY. Moreover, psm expression is uncoupled from expression of the quorum sensing system Agr, the main known psm activator. The expression of central genes of the oxidative stress response protects the bacteria from anticipated ROS stress derived from PSMs or exogenous sources. Thus, we identified a new link between the stringent response and oxidative stress in S. aureus that is likely crucial for survival upon phagocytosis.

show abstract

Section: Discussionmentioning

confidence: 99%

Inducible expression of (pp)pGpp synthetases in Staphylococcus aureus is associated with activation of stress response genes

et al. 2020

View full text Add to dashboard Cite

show abstract

“…This ties αPSM expression to cell density. A second virulence-associated global regulator, MgrA, was recently shown to bind to the αPSM promoter and regulate expression of the αPSM operon ( 26 ). In contrast to AgrA, MgrA represses expression of the αPSM transcript.…”

Section: Discussionmentioning

confidence: 99%

The Small RNA Teg41 Regulates Expression of the Alpha Phenol-Soluble Modulins and Is Required for Virulence in Staphylococcus aureus

Zapf

Wiemels

Keogh

et al. 2019

mBio

View full text Add to dashboard Cite

Small RNAs (sRNAs) remain an understudied class of regulatory molecules in bacteria in general and in Gram-positive bacteria in particular. In the major human pathogen Staphylococcus aureus, hundreds of sRNAs have been identified; however, only a few have been characterized in detail. In this study, we investigate the role of the sRNA Teg41 in S. aureus virulence. We demonstrate that Teg41, an sRNA divergently transcribed from the locus that encodes the cytolytic alpha phenol-soluble modulin (αPSM) peptides, plays a critical role in αPSM production. Overproduction of Teg41 leads to an increase in αPSM levels and a corresponding increase in hemolytic activity from S. aureus cells and cell-free culture supernatants. To identify regions of Teg41 important for its function, we performed an in silico RNA-RNA interaction analysis which predicted an interaction between the 3′ end of Teg41 and the αPSM transcript. Deleting a 24-nucleotide region from the S. aureus genome, corresponding to the 3′ end of Teg41, led to a 10-fold reduction in αPSM-dependent hemolytic activity and attenuation of virulence in a murine abscess model of infection. Restoration of hemolytic activity in the Teg41Δ3′ strain was possible by expressing full-length Teg41 in trans. Restoration of hemolytic activity was also possible by expressing the 3′ end of Teg41, suggesting that this region of Teg41 is necessary and sufficient for αPSM-dependent hemolysis. Our results show that Teg41 is positively influencing αPSM production, demonstrating for the first time regulation of the αPSM peptides by an sRNA in S. aureus. IMPORTANCE The alpha phenol-soluble modulins (αPSMs) are among the most potent toxins produced by Staphylococcus aureus. Their biological role during infection has been studied in detail; however, the way they are produced by the bacterial cell is not well understood. In this work, we identify a small RNA molecule called Teg41 that plays an important role in αPSM production by S. aureus. Teg41 positively influences αPSM production. The importance of Teg41 is highlighted by the fact that a strain containing a deletion in the 3′ end of Teg41 produces significantly less αPSMs and is attenuated for virulence in a mouse abscess model of infection. As the search for new therapeutic strategies to combat S. aureus infection proceeds, Teg41 may represent a novel target.

show abstract

“…In aggregate communities, S. aureus cells adjust the distribution of their adhesins and surface proteins to promote their tolerance of hazardous environments ( 5 , 6 ). Biofilm development and formation can be modulated by various regulatory factors such as sigma B ( 7 ), the Agr system ( 7 ), SaeRS ( 8 , 9 ), SarA ( 8 ), and MgrA ( 10 , 11 ), but the regulatory mechanisms of cell aggregation remain largely unknown.…”

Section: Introductionmentioning

confidence: 99%

SpoVG Modulates Cell Aggregation in Staphylococcus aureus by Regulating sasC Expression and Extracellular DNA Release

Zhu

Liu

Sun

2020

Appl Environ Microbiol

Self Cite

View full text Add to dashboard Cite

Biofilm formation is involved in numerous Staphylococcus aureus infections such as endocarditis, septic arthritis, osteomyelitis, and infections of indwelling medical devices. In these diseases, S. aureus forms biofilms as cell aggregates interspersed in host matrix material. Here, we have observed that the level of cell aggregation was significantly higher in the isogenic spoVG-deletion strain than in the wild-type strain. Reverse transcription-quantitative PCR data indicated that SpoVG could repress the expression of sasC, which codes for S. aureus surface protein C and is involved in cell aggregation and biofilm accumulation. Electromagnetic mobility shift assay demonstrated that SpoVG could specifically bind to the promoter region of sasC, indicating that SpoVG is a negative regulator and directly represses the expression of sasC. In addition, deletion of the SasC aggregation domain in the spoVG-deletion strain indicated that high-level expression of sasC could be the underlying cause of significantly increased cell aggregation formation. Our previous study showed that SpoVG is involved in oxacillin resistance of methicillin-resistant S. aureus by regulating the expression of genes involved in cell wall synthesis and degradation. In this study, we also found that SpoVG was able to negatively modulate the S. aureus drug tolerance under conditions of a high concentration of oxacillin treatment. These findings can broaden our understanding of the regulation of biofilm formation and drug tolerance in S. aureus. IMPORTANCE This study revealed that SpoVG can modulate cell aggregation by repressing sasC expression and extracellular DNA (eDNA) release. Furthermore, we have demonstrated the potential linkage between cell aggregation and antibiotic resistance. Our findings provide novel insights into the regulatory mechanisms of SpoVG involved in cell aggregation and in biofilm development and formation in Staphylococcus aureus.

show abstract

MgrA Negatively Regulates Biofilm Formation and Detachment by Repressing the Expression of psm Operons in Staphylococcus aureus

Cited by 40 publications

References 50 publications

Inducible expression of (pp)pGpp synthetases in Staphylococcus aureus is associated with activation of stress response genes

Inducible expression of (pp)pGpp synthetases in Staphylococcus aureus is associated with activation of stress response genes

The Small RNA Teg41 Regulates Expression of the Alpha Phenol-Soluble Modulins and Is Required for Virulence in Staphylococcus aureus

SpoVG Modulates Cell Aggregation in Staphylococcus aureus by Regulating sasC Expression and Extracellular DNA Release

Contact Info

Product

Resources

About