TatD DNases Contribute to Biofilm Formation and Virulence in Trueperella pyogenes

Zhang, Zehui; Yh, Liang; Yu, Li-Hui; Chen, Menghan; Guo, Yongfeng; Kang, Zhiruo; Qu, Chenghu; Tian, Chunlian; Zhang, Dexian; Ming-chun, Liu

doi:10.3389/fmicb.2021.758465

Cited by 9 publications

(14 citation statements)

References 42 publications

(55 reference statements)

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“…TatD DNases can participate in the immune-evasion process of pathogens and affect their pathogenicity [ 14 , 15 ]. We have previously found that TatD DNases could promote biofilm formation and virulence in T. pyogenes [ 16 ]. Thus, inhibiting the production and activity of TatD DNases is beneficial for reducing the biofilm formation and preventing the virulence of T. pyogenes .…”

Section: Discussionmentioning

confidence: 99%

“…We have previously predicted that His106 may be involved in binding metal ions in TatD960 and probably plays a key role in the catalytic reaction. In TatD825, His164 is assumed to bind to metal ions to promote enzymatic reactions, while Asp212 is a critical amino acid residue for TatD825 to perform its function in the degradation of DNA [ 16 ]. In this study, our data suggest that luteolin can bind to His106 of TatD960 by forming a hydrogen bond.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, TatD DNases have been proven to be involved in the biofilm formation of T . pyogenes [ 16 ]. Therefore, it can be speculated that the inhibition of TatD DNases after luteolin treatment may lead to a reduction in biofilms of T .…”

Section: Discussionmentioning

confidence: 99%

“…After SDS-PAGE, the proteins were transferred onto PVDF membranes (Millipore, Shanghai, China) by wet-blotting system. Membranes were blocked with 5% bovine serum albumin (BSA; Solarbio) in TBST buffer at 4 °C for 24 h. The anti-TatD960 polyclonal antibody (1:1000) and anti-TatD825 polyclonal antibody (1:1000) were prepared in the previous study and used as primary antibodies [ 16 ]. An HRP-labelled goat anti-rabbit IgG (1:10,000; Abcam, Shanghai, China) was used as the secondary antibody.…”

Section: Methodsmentioning

confidence: 99%

“…We have previously found that TatD960 and TatD825 are Mg 2+ -dependent DNases related to the virulence of T. pyogenes . Furthermore, TatD DNases could promote biofilm formation in T. pyogenes [ 16 ]. The result indicated that TatD DNases could be used as potential targets for developing drugs against virulence and biofilm formation in T. pyogenes .…”

Section: Introductionmentioning

confidence: 99%

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Molecular Basis for Luteolin as a Natural TatD DNase Inhibitor in Trueperella pyogenes

Zhang

Guo

et al. 2022

IJMS

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TatD960 and TatD825 are DNases that contribute to biofilm formation and virulence in Trueperella pyogenes (T. pyogenes). Luteolin is a natural flavonoid commonly found in plants that exhibits antimicrobial capacity. Our study aims to investigate the effects of luteolin on TatD DNases as a natural inhibitor. In this research, the expression of tatD genes and TatD proteins in T. pyogenes treated with luteolin was detected, and then the effect of luteolin on the hydrolysis of DNA by TatD DNases was analyzed using agarose gel electrophoresis. Moreover, the interactions between luteolin and TatD DNases were tested using surface plasmon resonance (SPR) assays and molecular docking analysis. After 1/2 MIC luteolin treatment, the transcription of tatD genes and expression of TatD proteins appeared to be reduced in 80–90% of T. pyogenes (n = 20). The gel assay revealed that luteolin can inhibit the activity of TatD DNases. The SPR assay showed that the KD values of luteolin to TatD960 and TatD825 were 6.268 × 10−6 M and 5.654 × 10−6 M, respectively. We found through molecular docking that hydrogen bonding is predominant in the interaction of luteolin and TatD DNases. Our data indicate that luteolin inhibited the ability of TatD DNases by decreasing their binding to DNA. The current study provides an insight into the development of luteolin as a DNase inhibitor in preventing biofilm formation and virulence in T. pyogenes.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Molecular Basis for Luteolin as a Natural TatD DNase Inhibitor in Trueperella pyogenes

Zhang

Guo

et al. 2022

IJMS

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TATDN2 resolution of R-loops is required for survival of BRCA1-mutant cancer cells

Jaiswal,

Dutta,

Srinivasan

et al. 2023

Nucleic Acids Research

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BRCA1-deficient cells have increased IRE1 RNase, which degrades multiple microRNAs. Reconstituting expression of one of these, miR-4638–5p, resulted in synthetic lethality in BRCA1-deficient cancer cells. We found that miR-4638-5p represses expression of TATDN2, a poorly characterized member of the TATD nuclease family. We discovered that human TATDN2 has RNA 3′ exonuclease and endonuclease activity on double-stranded hairpin RNA structures. Given the cleavage of hairpin RNA by TATDN2, and that BRCA1-deficient cells have difficulty resolving R-loops, we tested whether TATDN2 could resolve R-loops. Using in vitro biochemical reconstitution assays, we found TATDN2 bound to R-loops and degraded the RNA strand but not DNA of multiple forms of R-loops in vitro in a Mg2+-dependent manner. Mutations in amino acids E593 and E705 predicted by Alphafold-2 to chelate an essential Mg2+ cation completely abrogated this R-loop resolution activity. Depleting TATDN2 increased cellular R-loops, DNA damage and chromosomal instability. Loss of TATDN2 resulted in poor replication fork progression in the presence of increased R-loops. Significantly, we found that TATDN2 is essential for survival of BRCA1-deficient cancer cells, but much less so for cognate BRCA1-repleted cancer cells. Thus, we propose that TATDN2 is a novel target for therapy of BRCA1-deficient cancers.

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A multifaceted interplay between virulence, drug resistance, and the phylogeographic landscape of Mycobacterium tuberculosis

Mokrousov,

Vinogradova,

Dogonadze

et al. 2023

Microbiol Spectr

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Latin-American Mediterranean (LAM) family is one of the most significant and global genotypes of Mycobacterium tuberculosis . Here, we used the murine model to study the virulence and lethality of the genetically and epidemiologically distinct LAM strains. The pathobiological characteristics of the four LAM strains (three drug resistant and one drug susceptible) and the susceptible reference strain H37Rv were studied in the C57BL/6 mouse model. The whole-genome sequencing was performed using the HiSeq Illumina platform, followed by bioinformatics and phylogenetic analysis. The susceptible strain H37Rv showed the highest virulence. Drug-susceptible LAM strain (spoligotype SIT264) was more virulent than three multidrug-resistant (MDR) strains (SIT252, SIT254, and SIT266). All three MDR isolates were low lethal, while the susceptible isolate and H37Rv were moderately/highly lethal. Putting the genomic, phenotypic, and virulence features of the LAM strains/spoligotypes in the context of their dynamic phylogeography over 20 years reveals three types of relationships between virulence, resistance, and transmission. First, the most virulent and more lethal drug-susceptible SIT264 increased its circulation in parts of Russia. Second, moderately virulent and pre-XDR SIT266 was prevalent in Belarus and continues to be visible in North-West Russia. Third, the low virulent and MDR strain SIT252 previously considered as emerging has disappeared from the population. These findings suggest that strain virulence impacts the transmission, irrespective of drug resistance properties. The increasing circulation of susceptible but more virulent and lethal strains implies that personalized TB treatment should consider not only resistance but also the virulence of the infecting M. tuberculosis strains. IMPORTANCE The study is multidisciplinary and investigates the epidemically/clinically important and global lineage of Mycobacterium tuberculosis , named Latin-American-Mediterranean (LAM), yet insufficiently studied with regard to its pathobiology. We studied different LAM strains (epidemic vs endemic and resistant vs susceptible) in the murine model and using whole-genome analysis. We also collected long-term, 20-year data on their prevalence in Eurasia. The findings are both expected and unexpected. (i) We observe that a drug-susceptible but highly virulent strain increased its prevalence. (ii) By contrast, the multidrug-resistant (MDR) but low-virulent, low-lethal strain (that we considered as emerging 15 years ago) has almost disappeared. (iii) Finally, an intermediate case is the MDR strain with moderate virulence that continues to circulate. We conclude that (i) the former and latter strains are the most hazardous and require close epidemiological monitoring, and (ii) personalized TB treatment should consider not only drug resistance but also the virulence of the infecting strains and development of anti-virulence drugs is warranted.

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TatD DNases Contribute to Biofilm Formation and Virulence in Trueperella pyogenes

Cited by 9 publications

References 42 publications

Molecular Basis for Luteolin as a Natural TatD DNase Inhibitor in Trueperella pyogenes

Molecular Basis for Luteolin as a Natural TatD DNase Inhibitor in Trueperella pyogenes

TATDN2 resolution of R-loops is required for survival of BRCA1-mutant cancer cells

A multifaceted interplay between virulence, drug resistance, and the phylogeographic landscape of Mycobacterium tuberculosis

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