Abstract
Novel therapeutics are needed to treat pathologies associated with the Clostridioides difficile binary toxin (CDT), particularly when C. difficile 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.
Highlights
More than 2.8 million people were infected in 2019 by antibiotic-resistant bacteria in the United States alone, causing over 35,000 deaths [1]
The differentiation of one difficile strain morphism (RFLP)-based method and is one method used to classify C. difficile strains into versus another is achieved by identifying changes in the pathogenicity locus (PaLoc), a what is termed as toxinotypes [9]
Unprocessed CDTa has an unstructured region that may be important for Clostridioides difficile binary toxin (CDT) assembly and/or its host cell entry based on studies with CDT and other binary toxins, including anthrax and iota toxins [22,23,24]
Summary
More than 2.8 million people were infected in 2019 by antibiotic-resistant bacteria in the United States alone, causing over 35,000 deaths [1]. C. difficile is a gram-positive anaerobic pathogen responsible for antibiotic-associated diarrhea and pseudomembranous colitis caused by reduced levels of symbiotic gut microbiota [2,3]. The transmission of this disease occurs primarily in the form of highly stable spores, via the fecal-oral route, and is highly prevalent in hospital and nursing home settings [1,2]. In addition to the major toxins, 5–30% of clinical C. difficile responsible for disorganizing the intestinal epithelial cells by glycosylation of isolates generate the binary toxin termed C.[5]. CDT was identified first in the clinical C. difficile isolates generate the binary toxin termed C. difficile transferase (CDT),C. difficile strain.
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