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Mechanistic insights into the inhibitory effect of theaflavins on virulence factors production in Streptococcus mutans.

ABSTRACT: Streptococcus mutans is the primary etiological agent associated with cariogenic process. The present study aimed to investigate the antibacterial and anti-virulence activities of theaflavins (TFs) to Streptococcus mutans UA159 as well as the underlying mechanisms. The results showed that TFs were capable of suppressing the acid production, cell adherence, water-insoluble exopolysaccharides production, and biofilm formation by S. mutans UA159 with a dosage-dependent manner while without influencing the cell growth. By a genome-wide transcriptome analysis (RNA-seq), we found that TFs attenuated the biofilm formation of S. mutans UA159 by inhibiting glucosyltransferases activity and the production of glucan-binding proteins (GbpB and GbpC) instead of directly blocking the expression of genes coding for glucosyltransferases. Further, TFs inhibited the expression of genes implicated in peptidoglycan synthesis, glycolysis, lipid synthesis, two-component system, signaling peptide transport (comA), oxidative stress response, and DNA replication and repair, suggesting that TFs suppressed the virulence factors of S. mutans UA159 by affecting the signal transduction and cell envelope stability, and weakening the ability of cells on oxidative stress resistance. In addition, an upregulated expression of the genes involved in protein biosynthesis, amino acid metabolism, and transport system upon TFs treatment indicated that cells increase the protein synthesis and nutrients uptake as one self-protective mechanism to cope with stress caused by TFs. The results of this study increase our current understanding of the anti-virulence activity of TFs on S. mutans and provide clues for the use of TFs in the prevention of dental caries.

SUBMITTER: Kong J

PROVIDER: S-EPMC8271058 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Streptococcus mutans is known as a key causative agent of dental caries. It metabolizes dietary carbohydrate to produce acids which reduce the environmental pH leading to tooth demineralization. The ability of this bacterium to tolerate acids coupled with acid production, allows its effective colonization in the oral cavity leading to the establishment of highly cariogenic plaque. For this reason, S. mutans is the only bacterium found in significantly higher numbers than other bacteria in the dental plaque. The aim of this study was to evaluate the effect of crude extract and methanolic fraction of Z. officinale against S. mutans virulence properties.We investigated in vitro and in vivo activity of crude extract and methanolic fraction at sub- MIC levels against cariogenic properties of S. mutans. We found that these extracts strongly inhibited a variety of virulence properties which are critical for its pathogenesis. The biofilm formation in S. mutans was found to be reduced during critical growth phases. Furthermore, the glucan synthesis and adherence was also found to be inhibited. Nevertheless, the insoluble glucan synthesis and sucrose dependent adherence were apparently more reduced as compared to soluble glucan synthesis and sucrose- independent adherence. Biofilm architecture inspected with the help of confocal and scanning electron microscopy, showed dispersion of cells in the treated group as compared to the control. The Quantitative Real Time PCR (qRT-PCR) data had shown the down regulation of the virulence genes, which is believed to be one of the major reasons responsible for the observed reduction in the virulence properties. The incredible reduction of caries development was found in treated group of rats as compared to the untreated group which further validate our in vitro data.The whole study concludes a prospective role of crude extract and methanolic fraction of Z. officinale in targeting complete array of cariogenic properties of S. mutans, thus reducing its pathogenesis. Hence, it may be strongly proposed as a putative anti- cariogenic agent.

Project description:Streptococcus mutans is a key cariogenic bacterium responsible for the initiation of tooth decay. Biofilm formation is a crucial virulence property. We discovered a putative glycosyltransferase, SMU_833, in S. mutans capable of modulating dynamic interactions between two key biofilm matrix components, glucan and extracellular DNA (eDNA). The deletion of smu_833 decreases glucan and increases eDNA but maintains the overall biofilm biomass. The decrease in glucan is caused by a reduction in GtfB and GtfC, two key enzymes responsible for the synthesis of glucan. The increase in eDNA was accompanied by an elevated production of membrane vesicles, suggesting that SMU_833 modulates the release of eDNA via the membrane vesicles, thereby altering biofilm matrix constituents. Furthermore, glucan and eDNA were colocalized. The complete deletion of gtfBC from the smu_833 mutant significantly reduced the biofilm biomass despite the elevated eDNA, suggesting the requirement of minimal glucans as a binding substrate for eDNA within the biofilm. Despite no changes in overall biofilm biomass, the mutant biofilm was altered in biofilm architecture and was less acidic in vitro Concurrently, the mutant was less virulent in an in vivo rat model of dental caries, demonstrating that SMU_833 is a new virulence factor. Taken together, we conclude that SMU_833 is required for optimal biofilm development and virulence of S. mutans by modulating extracellular matrix components. Our study of SMU_833-modulated biofilm matrix dynamics uncovered a new target that can be used to develop potential therapeutics that prevent and treat dental caries.IMPORTANCE Tooth decay, a costly and painful disease affecting the vast majority of people worldwide, is caused by the bacterium Streptococcus mutans The bacteria utilize dietary sugars to build and strengthen biofilms, trapping acids onto the tooth's surface and causing demineralization and decay of teeth. As knowledge of our body's microbiomes increases, the need for developing therapeutics targeted to disease-causing bacteria has arisen. The significance of our research is in studying and identifying a novel therapeutic target, a dynamic biofilm matrix that is mediated by a new virulence factor and membrane vesicles. The study increases our understanding of S. mutans virulence and also offers a new opportunity to develop effective therapeutics targeting S. mutans In addition, the mechanisms of membrane vesicle-mediated biofilm matrix dynamics are also applicable to other biofilm-driven infectious diseases.

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Mechanistic insights into the inhibitory effect of theaflavins on virulence factors production in Streptococcus mutans.

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