The CtsR regulator controls the expression of clpC, clpE and clpP and is required for the virulence of Enterococcus faecalis in an invertebrate model

Cassenego, Ana Paula Vaz; Oliveira, Naira Elane Moreira de; Laport, Marinella Silva; Abranches, Jacqueline; Lemos, José A.; Giambiagi-deMarval, Márcia

doi:10.1007/s10482-016-0727-0

Cited by 16 publications

(13 citation statements)

References 21 publications

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“…However, we found that the ΔclpP mutant strain decreased biofilm formation and increased virulence in a G. mellonella model. A previous study proposed that the CtsR regulator controlled the expression of clpC, clpE, and clpP and was required for the virulence of E. faecalis V583, but the role of clpP in the virulence of E. faecalis was still unclear [40]. The The data are given as the means of the results from two independent experiment.…”

Section: Discussionmentioning

confidence: 99%

ClpP participates in stress tolerance, biofilm formation, antimicrobial tolerance, and virulence of Enterococcus faecalis

Zheng

Wang

et al. 2020

BMC Microbiol

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Background: ClpP is important for bacterial growth and plays an indispensable role in cellular protein quality control systems by refolding or degrading damaged proteins, but the physiological significance of ClpP in Enterococcus faecalis remains obscure. A clpP deletion mutant (△clpP) was constructed using the E. faecalis OG1RF strain to clarify the effect of ClpP on E. faecalis. The global abundance of proteins was determined by a mass spectrometer with tandem mass tag labeling. Results: The ΔclpP mutant strain showed impaired growth at 20°C or 45°C at 5% NaCl or 2 mM H 2 O 2 . The number of surviving ΔclpP mutants decreased after exposure to the high concentration (50× minimal inhibitory concentration) of linezolid or minocycline for 96 h. The ΔclpP mutant strain also demonstrated decreased biofilm formation but increased virulence in a Galleria mellonella model. The mass spectrometry proteomics data indicated that the abundances of 135 proteins changed (111 increased, 24 decreased) in the ΔclpP mutant strain. Among those, the abundances of stress response or virulence relating proteins: FsrA response regulator, gelatinase GelE, regulatory protein Spx (spxA), heat-inducible transcription repressor HrcA, transcriptional regulator CtsR, ATPase/ chaperone ClpC, acetyl esterase/lipase, and chaperonin GroEL increased in the ΔclpP mutant strain; however, the abundances of ribosomal protein L4/L1 family protein (rplD), ribosomal protein L7/L12 (rplL2), 50S ribosomal protein L13 (rplM), L18 (rplR), L20 (rplT), 30S ribosomal protein S14 (rpsN2) and S18 (rpsR) all decreased. The abundances of biofilm formation-related adapter protein MecA increased, while the abundances of dihydroorotase (pyrC), orotate phosphoribosyltransferase (pyrE), and orotidine-5′-phosphate decarboxylase (pyrF) all decreased in the ΔclpP mutant strain. Conclusion:The present study demonstrates that ClpP participates in stress tolerance, biofilm formation, antimicrobial tolerance, and virulence of E. faecalis.

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Section: Discussionmentioning

confidence: 99%

ClpP participates in stress tolerance, biofilm formation, antimicrobial tolerance, and virulence of Enterococcus faecalis

Zheng

Wang

et al. 2020

BMC Microbiol

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“…However, we found that the ΔclpP mutant strain decreased biofilm formation and increased virulence in a G. mellonella model. A previous study proposed that the CtsR regulator controlled the expression of clpC, clpE, and clpP and was required for the virulence of E. faecalis V583, but the role of clpP in the virulence of E. faecalis was still unclear [40]. The FsrABDC signal transduction system and GelE are major virulence factors in E. faecalis [41,42].…”

Section: Discussionmentioning

confidence: 99%

ClpP participates in stress tolerance, biofilm formation, antimicrobial tolerance, and virulence of Enterococcus faecalis

Zheng

Wang

et al. 2020

Preprint

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Background ClpP is important for bacterial growth and plays an indispensable role in cellular protein quality control systems by refolding or degrading damaged proteins, but the physiological significance of ClpP in Enterococcus faecalis remains obscure. A clpP deletion mutant (△ clpP ) was constructed using the E. faecalis OG1RF strain to clarify the effect of ClpP on E. faecalis. The global abundance of proteins was determined by a mass spectrometer with tandem mass tag labeling.Results The Δ clpP mutant strain showed impaired growth at 20°C or 45°C at 5% NaCl or 2 mM H 2 O 2 . The number of surviving Δ clpP mutants decreased after exposure to the high concentration (50× minimal inhibitory concentration) of linezolid or minocycline for 96 h. The Δ clpP mutant strain also demonstrated decreased biofilm formation but increased virulence in a Galleria mellonella model. The mass spectrometry proteomics data indicated that the abundances of 135 proteins changed (111 increased, 24 decreased) in the Δ clpP mutant strain. Among those, the abundances of stress response or virulence relating proteins: FsrA response regulator, gelatinase GelE, regulatory protein Spx ( spxA ), heat-inducible transcription repressor HrcA, transcriptional regulator CtsR, ATPase/chaperone ClpC, acetyl esterase/lipase, and chaperonin GroEL increased in the Δ clpP mutant strain; however, the abundances of ribosomal protein L4/L1 family protein ( rplD ), ribosomal protein L7/L12 ( rplL2 ), 50S ribosomal protein L13 ( rplM ), L18 ( rplR ), L20 ( rplT ), 30S ribosomal protein S14 ( rpsN2 ) and S18 ( rpsR ) all decreased. The abundances of biofilm formation-related adapter protein MecA increased, while the abundances of dihydroorotase ( pyrC ), orotate phosphoribosyltransferase ( pyrE ), and orotidine-5'-phosphate decarboxylase ( pyrF ) all decreased in the Δ clpP mutant strain.Conclusion The present study demonstrates that ClpP participates in stress tolerance, biofilm formation, antimicrobial tolerance, and virulence of E. faecalis.

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“…ClpXP has been identified as a promising target for drug development due to its significant role in regulating virulence in diverse pathogens [19][20][21][22]133,134 . Pioneering work has uncovered synthetic β-lactone-, phenyl ester-, and boronate-based inhibitors of ClpXP [135][136][137] .…”

Section: Discussionmentioning

confidence: 99%

“…Of the remaining proteins, several factors directed us to ClpP, the proteolytic component of the ClpXP protease, as a direct biochemical target. ClpXP plays an integral role in bacterial viability by degrading damaged and misfolded proteins, and is strongly associated with bacterial virulence in multiple Gram-positive pathogens including S. aureus, S. pneumoniae, and E. faecalis [18][19][20][21][22] . A further examination of our quantitative proteomics dataset also showed that 1 treatment led to at least a 2-fold enrichment of a number of known or suspected protein substrates of ClpP [23][24][25][26][27] ( Figure S1).…”

Section: Target Discovery By Inhibitor Capturementioning

confidence: 99%

Armeniaspirols inhibit the AAA+ proteases ClpXP and ClpYQ leading to cell division arrest in Gram-positive bacteria

Labana

Dornan

Lafreniere

et al. 2019

Preprint

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The emergence of multi-drug resistant organisms clinically presents major challenges to managing human health and threaten the great progress that has been made in preventing morbidity in the age of antibiotics. In order to combat these pathogens, new antibiotics with diverse mechanisms of action will be required. Armeniaspirols represent a novel class of natural product-based antibiotic molecules with unknown mechanisms of action. Herein, we synthesized analogs of armeniaspirol and studied their antibiotic properties and mechanism of action. Using a combination of chemoproteomics, quantitative proteomics, and a battery of functional assays we discovered that armeniaspirols inhibit the bacterial divisome through direct inhibition of the ClpYQ and ClpXP proteases. This was validated by comparisons with genetic knockouts. Sub-lethal challenges suggested that resistance to armeniaspirol inhibition of ClpYQ and ClpXP proteases was difficult to achieve without catastrophic consequences for the bacteria. Thus, the armeniaspirols represent an important new tool to combat multi-drug resistance, through a potent and highly novel mechanism of action.

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The CtsR regulator controls the expression of clpC, clpE and clpP and is required for the virulence of Enterococcus faecalis in an invertebrate model

Cited by 16 publications

References 21 publications

ClpP participates in stress tolerance, biofilm formation, antimicrobial tolerance, and virulence of Enterococcus faecalis

ClpP participates in stress tolerance, biofilm formation, antimicrobial tolerance, and virulence of Enterococcus faecalis

ClpP participates in stress tolerance, biofilm formation, antimicrobial tolerance, and virulence of Enterococcus faecalis

Armeniaspirols inhibit the AAA+ proteases ClpXP and ClpYQ leading to cell division arrest in Gram-positive bacteria

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