The Importance of Therapeutically Targeting the Binary Toxin from

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2021 Apr 3

PMID 33805767

Citations 10

Authors

Dinendra L Abeyawardhane

Raquel Godoy-Ruiz

Kaylin A Adipietro

Kristen M Varney

Richard R Rustandi

Edwin Pozharski

David J Weber

Affiliations

Soon will be listed here.

Abstract

Novel therapeutics are needed to treat pathologies associated with the binary toxin (CDT), particularly when infection (CDI) occurs in the elderly or in hospitalized patients having illnesses, in addition to CDI, such as cancer. While therapies are available to block toxicities associated with the large clostridial toxins (TcdA and TcdB) in this nosocomial disease, nothing is available yet to treat toxicities arising from strains of CDI having the binary toxin. Like other binary toxins, the active CDTa catalytic subunit of CDT is delivered into host cells together with an oligomeric assembly of CDTb subunits via host cell receptor-mediated endocytosis. Once CDT arrives in the host cell's cytoplasm, CDTa catalyzes the ADP-ribosylation of G-actin leading to degradation of the cytoskeleton and rapid cell death. Although a detailed molecular mechanism for CDT entry and host cell toxicity is not yet fully established, structural and functional resemblances to other binary toxins are described. Additionally, unique conformational assemblies of individual CDT components are highlighted herein to refine our mechanistic understanding of this deadly toxin as is needed to develop effective new therapeutic strategies for treating some of the most hypervirulent and lethal strains of CDT-containing strains of CDI.

Citing Articles

Structural and Functional Insights into the Delivery Systems of and Clostridial Binary Toxins.

Sevdalis S, Varney K, Cook M, Gillespie J, Pozharski E, Weber D Toxins (Basel). 2024; 16(8).

PMID: 39195740 PMC: 11359772. DOI: 10.3390/toxins16080330.

Exploring the Toxin-Mediated Mechanisms in Infection.

Pourliotopoulou E, Karampatakis T, Kachrimanidou M Microorganisms. 2024; 12(5).

PMID: 38792835 PMC: 11124097. DOI: 10.3390/microorganisms12051004.

Domperidone Protects Cells from Intoxication with Toxins by Inhibiting Hsp70-Assisted Membrane Translocation.

Braune-Yan M, Jia J, Wahba M, Schmid J, Papatheodorou P, Barth H Toxins (Basel). 2023; 15(6).

PMID: 37368685 PMC: 10305128. DOI: 10.3390/toxins15060384.

Structural Basis for Binding of Neutralizing Antibodies to Binary Toxin.

Goldsmith J, Dewar V, Hermand P, Blais N, McLellan J J Bacteriol. 2023; 205(4):e0045622.

PMID: 36951574 PMC: 10127577. DOI: 10.1128/jb.00456-22.

Cytotoxic synergism of toxin B with proinflammatory cytokines in subjects with inflammatory bowel diseases.

Bassotti G, Fruganti A, Stracci F, Marconi P, Fettucciari K World J Gastroenterol. 2023; 29(4):582-596.

PMID: 36742168 PMC: 9896618. DOI: 10.3748/wjg.v29.i4.582.

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