Functional and Biochemical Characterization of the MazEF6 Toxin-Antitoxin System of Mycobacterium tuberculosis

Chattopadhyay, Gopinath; Bhasin, Munmun; Ahmed, Shahbaz; Gosain, Tannu Priya; Ganesan, Srivarshini; Das, Sayan; Thakur, Chandrani; Chandra, Nagasuma; Singh, Ramandeep; Varadarajan, Raghavan

doi:10.1128/jb.00058-22

Cited by 12 publications

(10 citation statements)

References 104 publications

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“…It is expected that the C-terminal domain of MazE6 would become ordered when it neutralizes MazF6. Autoregulation of mazEF6 operon via feedback inhibition can occur by binding of either MazE6 or by MazEF6 TA complex, wherein the latter exerts a more stringent control 37,51 . Given the pathological significance of Mtb and the role of TA systems in the pathology and virulence of the organism, the sequences upstream of TSS of 2388 annotated coding genes of Mtb were further examined by Cortes et al, to determine consensus operator sequences, if any 43 .…”

Section: Discussionmentioning

confidence: 99%

Structural and mutational analysis of MazE6-operator DNA complex provide insights into autoregulation of toxin-antitoxin systems

Kumari

Sarma

2022

Commun Biol

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Of the 10 paralogs of MazEF Toxin-Antitoxin system in Mycobacterium tuberculosis, MazEF6 plays an important role in multidrug tolerance, virulence, stress adaptation and Non Replicative Persistant (NRP) state establishment. The solution structures of the DNA binding domain of MazE6 and of its complex with the cognate operator DNA show that transcriptional regulation occurs by binding of MazE6 to an 18 bp operator sequence bearing the TANNNT motif (-10 region). Kinetics and thermodynamics of association, as determined by NMR and ITC, indicate that the nMazE6-DNA complex is of high affinity. Residues in N-terminal region of MazE6 that are key for its homodimerization, DNA binding specificity, and the base pairs in the operator DNA essential for the protein-DNA interaction, have been identified. It provides a basis for design of chemotherapeutic agents that will act via disruption of TA autoregulation, leading to cell death.

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Section: Discussionmentioning

confidence: 99%

Structural and mutational analysis of MazE6-operator DNA complex provide insights into autoregulation of toxin-antitoxin systems

Kumari

Sarma

2022

Commun Biol

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“…MA1-980-A647) was used. Affinity of individual ICabs for QacA D411N on the yeast cell surface was estimated using flowcytometry as described in earlier studies 24,37 .…”

Section: Methodsmentioning

confidence: 99%

CryoEM structure of QacA, an antibacterial efflux transporter from Staphylococcus aureus

Majumder

Ahmed

Ahuja

et al. 2022

Preprint

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Efflux of antibacterial compounds is a major mechanism for developing antimicrobial resistance. In the Gram-positive pathogen Staphylococcus aureus, QacA, a 14 transmembrane (TM) helix containing major facilitator superfamily antiporter, mediates proton-coupled efflux of mono and divalent cationic antibacterial compounds. In this study, we report the cryoEM structure of QacA, with a single mutation D411N that improves homogeneity and retains efflux activity against divalent cationic compounds like dequalinium and chlorhexidine. The structure of substrate-free QacA, complexed to two single-domain camelid antibodies, was elucidated to a resolution of 3.6 &Aring. The structure displays an outward-open conformation with an extracellular hairpin loop, which is conserved in a subset of DHA2 transporters and its deletion causes a loss of function in the transporter. Modelling and simulations of QacA's cytosol-facing and occluded conformations reveal asymmetry in the rocker-switch mode of QacA's conformational shifts, providing new insights into the organisation and structural dynamics of DHA2 members.

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“… 66 To bypass the toxin, phages can encode antitoxins. 67 , 68 Antitoxins can compete for the same binding site of toxins to disable their function. Alternatively, antitoxins can be chosen to neutralize the toxicity of toxins.…”

Section: (V) Bacterial Infection Through the Abi System Leads To Fail...mentioning

confidence: 99%

Intestinal phages interact with bacteria and are involved in human diseases

Han

Ding

2022

Gut Microbes

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Phages are the most abundant and diverse biological entities on Earth and exert specific effects on bacterial hosts. The coexistence of phages and bacteria in the intestinal tract is dynamic and interdependent. Phages are involved in maintaining the stability and composition of the bacterial community, and an imbalance in phages and bacteria in the intestinal tract can cause diseases. This review elucidates interactions between phages and bacteria in the human intestinal tract and their roles in the pathogenesis and treatment of diseases. Understanding the relationship among phages, bacteria and host diseases is conducive to promoting the application of phages in the treatment of human diseases. List of abbreviations EMBL-EBI The European Bioinformatics Institute; E. coli Escherichia coli; E. faecalis Enterobacter faecalis; B. fragilis Bacteroides fragilis; B. vulgatus Bacteroides vulgatus; SaPIs Staphylococcus aureus pathogenicity islands; ARGs Antibiotic resistance genes; STEC Shiga toxigenic E. coli; Stx Shiga toxin; BLAST Basic Local Alignment Search Tool; TSST-1 Toxic shock toxin 1; RBPs Receptor-binding proteins; LPS lipopolysaccharide; OMVs Outer membrane vesicles; PT Phosphorothioate; BREX Bacteriophage exclusion; OCR Overcome classical restriction; Pgl Phage growth limitation; DISARM Defense island system associated with restrictionmodification; R-M system Restriction-modification system; BREX system Bacteriophage exclusion system; CRISPR Clustered regularly interspaced short palindromic repeats; Cas CRISPR-associated; PAMs Prospacer adjacent motifs; crRNA CRISPR RNA; SIE; OMPs; Superinfection exclusion; Outer membrane proteins; Abi Abortive infection; TA Toxin-antitoxin; TLR Toll-like receptor; APCs Antigen-presenting cells; DSS Dextran sulfate sodium; IELs Intraepithelial lymphocytes; FMT Fecal microbiota transfer; IFN-γ Interferon-gamma; IBD Inflammatory bowel disease; AgNPs Silver nanoparticles; MDSC Myeloid-derived suppressor cell; CRC Colorectal cancer; VLPs Virus-like particles; TMP Tape measure protein; PSMB4 Proteasome subunit beta type-4; ALD Alcohol-related liver disease; GVHD Graft-versus-host disease; ROS Reactive oxygen species; RA Rheumatoid arthritis; CCP Cyclic citrullinated protein; AMGs Accessory metabolic genes; T1DM Type 1 diabetes mellitus; T2DM Type 2 diabetes mellitus; SCFAs Short-chain fatty acids; GLP-1 Glucagon-like peptide-1; A. baumannii Acinetobacter baumannii; CpG Deoxycytidylinate-phosphodeoxyguanosine; PEG Polyethylene glycol; MetS Metabolic syndrome; OprM Outer membrane porin M.

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Functional and Biochemical Characterization of the MazEF6 Toxin-Antitoxin System of Mycobacterium tuberculosis

Cited by 12 publications

References 104 publications

Structural and mutational analysis of MazE6-operator DNA complex provide insights into autoregulation of toxin-antitoxin systems

Structural and mutational analysis of MazE6-operator DNA complex provide insights into autoregulation of toxin-antitoxin systems

CryoEM structure of QacA, an antibacterial efflux transporter from Staphylococcus aureus

Intestinal phages interact with bacteria and are involved in human diseases

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