CovR Alleviates Transcriptional Silencing by a Nucleoid-Associated Histone-Like Protein in Streptococcus mutans

Biswas, Indranil; Mohapatra, Saswat S.

doi:10.1128/jb.06812-11

Cited by 10 publications

(14 citation statements)

References 79 publications

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“…In addition to strain differences in gene content, our high-resolution analysis revealed the important role that mobile elements have in the variability of the CovR transcriptomes (21, 25, 26). Previously, CovR has been proposed to silence a large genomic island in Streptococcus mutans (57). Notably, the S. mutans CovR is an orphan regulator which has lost its cognate histidine kinase CovS and, consequently, the CovR function is independent of its phosphorylation (57, 58).…”

Section: Discussionmentioning

confidence: 99%

The CovR regulatory network drives the evolution of Group BStreptococcusvirulence

Mazzuoli

Daunesse

Varet

et al. 2021

Preprint

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Virulence of the neonatal pathogen Group B Streptococcus depends on the master regulator CovR. Inactivation of CovR leads to large-scale transcriptome remodeling and impairs almost every step of the interaction between the pathogen and the host. However, comparative analyses suggested a plasticity of the CovR signalling pathway in clinical isolates, probably due to the host selective pressure and leading to phenotypic heterogeneity in the bacterial population. Here, we characterize the CovR regulatory network in a strain representative of the hypervirulent lineage responsible of the majority of late-onset meningitidis. Genome-wide binding and transcriptome analysis demonstrated that CovR acts as a direct and global repressor of virulence genes, either as a primary regulator or with specialized co-regulators. Remarkably, CovR directly regulates genes of the pan-genome, including the two specific hypervirulent adhesins and horizontally acquired genes, as well as core-genes showing mutational biases in the population. Parallel analysis of the CovR network in a second isolate links strain-specificities to micro-evolutions in CovR-regulated promoters and to broad difference due to variability in CovR activation by phosphorylation. Our results highlight the direct, coordinated, and strain-specific regulation of virulence genes by CovR. This intra-species evolution of the signalling network reshapes bacterial-host interactions, increasing the potential for adaptation and the emergence of clone associated with specific diseases.

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Section: Discussionmentioning

confidence: 99%

The CovR regulatory network drives the evolution of Group BStreptococcusvirulence

Mazzuoli

Daunesse

Varet

et al. 2021

Preprint

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“…Plasmid pIB-B39 contains the hlp gene from S. mutans, which was cloned into NdeI and XhoI sites to produce C-terminally His-tagged HLP (Biswas & Mohapatra, 2012). The plasmid was transformed into E. coli BL21(DE3)/pLysS cells and the production of HLP-His was induced by the addition of isopropyl -d-1-thiogalactopyranoside (IPTG).…”

Section: Protein Expression and Purificationmentioning

confidence: 99%

“…In contrast to E. coli HU, streptococcal HLP is essential for survival (Bugrysheva et al, 2011;; therefore, it is a potential target for drug development. Streptococcal HLP bind to DNA nonspecifically, although certain streptococcal HLPs have a preference for AT-rich DNA Biswas & Mohapatra, 2012). We and other researchers have also shown that streptococcal HLP also participates in gene transcription by binding to the target DNA (Liu Crystals of SmuHLP obtained from Wizard 1 condition A5.…”

Section: Introductionmentioning

confidence: 99%

Crystal structure of histone-like protein fromStreptococcus mutansrefined to 1.9 Å resolution

et al. 2016

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Nucleoid-associated proteins (NAPs) in prokaryotes play an important architectural role in DNA bending, supercoiling and DNA compaction. In addition to architectural roles, some NAPs also play regulatory roles in DNA replication and repair, and act as global transcriptional regulators in many bacteria. Bacteria encode multiple NAPs and some of them are even essential for survival.Streptococcus mutans, a dental pathogen, encodes one such essential NAP called histone-like protein (HLP). Here, the three-dimensional structure ofS. mutansHLP has been determined to 1.9 Å resolution. The HLP structure is a dimer and shares a high degree of similarity with other bacterial NAPs, including HU. Since HLPs are essential for the survival of pathogenic streptococci, this structure determination is potentially beneficial for future drug development against these pathogens.

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“…The binding of streptococcal HLP to heart and kidney basement membranes was also reported and it was found to be highly immunogenic [10]. But unlike HU of E. coli, streptococcal HLP was shown to be essential for the survival of the pathogen [13,14]. Due to these reasons, streptococcal HLP is considered as a potential drug target.…”

Section: Introductionmentioning

confidence: 99%

In Silico Drug Repurposing to Target Histone-Like Protein of Streptococcus Mutans

Marimuthu¹,

Rosy²,

Thangamariappan³

et al. 2019

IJEAT

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Streptococcus mutans, in spite of its natural occurrence in human oral cavity, causes dental caries and rarely, in some complications, infective endocarditis. Development of vaccines or drugs to prevent or control these organisms has been under study. Histone-like protein (HLP), a nucleoid associated protein, is found essential for the survival and virulence of these pathogens. We have employed an in silico approach to specifically target the HLP of Streptococcus mutans with available approved drugs from DrugBank. Computational analysis showed conserved regions in DNA-binding domain of the S. mutans HLP and its homologues in 47-49 and 78-79 residues. The S. mutans HLP was found to be closely related within streptococcal species in phylogenetic analysis. Alanine and lysine were found to be higher in the protein which is the characteristic of histone-like proteins. The crystal structure of S. mutans HLP is similar to HLP from Mycobacterium tuberculosis despite their sequential variations and evolutionary distance. Etravirine, Abacavir, Adenosine phosphate, Flucloxacillin, Nelarabine, and Regadenoson were found to efficiently bind at the DNA binding domain of S. mutans HLP. From these results it can be concluded that these drugs can be repurposed to control streptococcal infections.

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CovR Alleviates Transcriptional Silencing by a Nucleoid-Associated Histone-Like Protein in Streptococcus mutans

Cited by 10 publications

References 79 publications

The CovR regulatory network drives the evolution of Group BStreptococcusvirulence

The CovR regulatory network drives the evolution of Group BStreptococcusvirulence

Crystal structure of histone-like protein fromStreptococcus mutansrefined to 1.9 Å resolution

In Silico Drug Repurposing to Target Histone-Like Protein of Streptococcus Mutans

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