Special Issue "Inhibitors and Countermeasures against Bacterial and Plant Toxins"

A special issue of Toxins (ISSN 2072-6651).

Deadline for manuscript submissions: 31 August 2020.

Special Issue Editors

Dr. Daniel Gillet
Website
Guest Editor
Service d'Ingénierie Moléculaire des Protéines (SIMOPRO), JOLIOT, CEA, Université Paris-Saclay, F-91191 Gif Sur Yvette, France
Interests: toxins, bacterial toxins, diphtheria toxin, ricin toxin, Shiga toxins, botulinum toxins, CBRN, Biodefense
Special Issues and Collections in MDPI journals
Dr. Julien Barbier
Website
Guest Editor
Service d'Ingénierie Moléculaire des Protéines (SIMOPRO), JOLIOT, CEA, Université Paris-Saclay, F-91191 Gif Sur Yvette, France
Interests: ricin; Shiga toxins; bacterial toxins; retrograde transport; toxin inhibitors
Special Issues and Collections in MDPI journals

Special Issue Information

Dear Colleagues,

Inhibitors of bacterial and plant toxins are used as research tools to understand the mechanism of action of toxins. Inhibitors also form the basis for the development of drugs to treat intoxications and bacterial infections. Thus, inhibitors are central to the field of toxinology.

During bacterial infections of host organisms, protein toxins are among the most important virulence factors used by the bacteria to invade, survive, and expand in a rich nutritive, but also hostile, environment. These toxins may contain all the components necessary to achieve their deleterious effects or can be effector proteins injected into host cells through diverse and complex secretion systems acting as transmembrane injectors. Microorganisms also fight each other with toxins to secure their existence in their ecological niche and protect themselves from their own toxins with natural inhibitors called antitoxins. Plants produce protein toxins that resemble bacterial toxins in their architecture and mechanisms of action. These toxins may play a role of defense against infection or predation. They are also the cause of accidental, voluntary or criminal poisoning.

There is an extraordinary diversity of bacterial and plant toxins. Likewise, there is a high diversity of toxin substrates and mechanisms leading to cellular perturbations. The actions of these toxins may include the perforation of membranes, the manipulation of the cytoskeleton and/or of signaling pathways, the diversion of protein trafficking, the impairment of neuromediator secretion, the inhibition of protein synthesis, the deregulation of transcription, the damaging of DNA, and many other effects. As a result, toxins may paralyze or kill cells, open cellular barriers, manipulate the host’s immune defenses to favor bacterial invasion or persistence in tissues, or kill the infected organism as a whole.

After less than a century of relative relief from mortal bacterial infections thanks to antibiotics, the development of bacterial strains resistant to multiple antibiotics has induced a re-emergence of infectious diseases. Infections become untreatable, inducing 700,000 deaths per year worldwide. Vaccines against toxins have helped to reduce dramatically the prevalence of a series of fatal bacterial diseases such as diphtheria, tetanus or whooping cough. However, lack of, or breaches in vaccination coverage result in the resurgence of these mortal diseases. In addition, some less frequent toxin infections never benefited from efficient treatment or vaccines. In the past, highly pathogenic bacterial and plant toxins as well as toxin-producing bacteria have been weaponized and used in warfare. They are now involved in terrorist threats and criminal or suicidal actions. Thus, altogether, there is an urgent need for countermeasures to neutralize and treat intoxications and infections involving bacterial and plant toxins.

This Special Issue proposes to highlight, through reviews, research articles, and communications, as well as opinion statements, novel concepts and molecular developments to inhibit the effects of bacterial and plant toxins and understand their mechanisms of action. Inhibitors and countermeasures are taken here in their broader meaning. They can be natural or synthetic small molecule inhibitors acting on toxins or on pathways exploited by toxins; they can be peptides, proteins, or of another chemical nature; they enclose monoclonal, polyclonal or engineered antibodies, vaccines, or other means to counteract the action of toxins. Contributions may address fundamental aspects, drug discovery and development, clinical evaluation or any other domains of toxinology.

Dr. Daniel Gillet
Dr. Julien Barbier
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a double-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Toxins is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2000 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Toxin Inhibitors;
  • Toxin countermeasures;
  • Bacterial infections;
  • Bacterial Toxin;
  • Plant toxins.

Published Papers (3 papers)

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Research

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Open AccessArticle
A Humanized Monoclonal Antibody Cocktail to Prevent Pulmonary Ricin Intoxication
Toxins 2020, 12(4), 215; https://doi.org/10.3390/toxins12040215 - 29 Mar 2020
Abstract
PB10 IgG1, a monoclonal antibody (MAb) directed against an immunodominant epitope on the enzymatic subunit (RTA) of ricin toxin (RT), has been shown to passively protect mice and non-human primates from an aerosolized lethal-dose RT challenge. However, it was recently demonstrated [...] Read more.
PB10 IgG1, a monoclonal antibody (MAb) directed against an immunodominant epitope on the enzymatic subunit (RTA) of ricin toxin (RT), has been shown to passively protect mice and non-human primates from an aerosolized lethal-dose RT challenge. However, it was recently demonstrated that the therapeutic efficacy of PB10 IgG1 is significantly improved when co-administered with a second MAb, SylH3, targeting RT’s binding subunit (RTB). Here we report that the PB10/SylH3 cocktail is also superior to PB10 alone when used as a pre-exposure prophylactic (PrEP) in a mouse model of intranasal RT challenge. The benefit of the PB10/SylH3 cocktail prompted us to engineer a humanized IgG1 version of SylH3 (huSylH3). The huPB10/huSylH3 cocktail proved highly efficacious in the mouse model, thereby opening the door to future testing in non-human primates. Full article
(This article belongs to the Special Issue Inhibitors and Countermeasures against Bacterial and Plant Toxins)
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Open AccessArticle
Revisiting Old Ionophore Lasalocid as a Novel Inhibitor of Multiple Toxins
Toxins 2020, 12(1), 26; https://doi.org/10.3390/toxins12010026 - 01 Jan 2020
Abstract
The ionophore lasalocid is widely used as a veterinary drug against coccidiosis. We found recently that lasalocid protects cells from two unrelated bacterial toxins, the cytotoxic necrotizing factor-1 (CNF1) from Escherichia. coli and diphtheria toxin. We evaluated lasalocid’s capacity to protect cells against [...] Read more.
The ionophore lasalocid is widely used as a veterinary drug against coccidiosis. We found recently that lasalocid protects cells from two unrelated bacterial toxins, the cytotoxic necrotizing factor-1 (CNF1) from Escherichia. coli and diphtheria toxin. We evaluated lasalocid’s capacity to protect cells against other toxins of medical interest comprising toxin B from Clostridium difficile, Shiga-like toxin 1 from enterohemorrhagic E. coli and exotoxin A from Pseudomonas aeruginosa. We further characterized the impact of lasalocid on the endolysosomal and the retrograde pathways and organelle integrity, especially the Golgi apparatus. We found that lasalocid protects cells from all toxins tested and impairs the drop of vesicular pH along the trafficking pathways that are required for toxin sorting and translocation to the cytoplasm. Lasalocid also has an impact on the cellular distribution of GOLPH4 and GOLPH2 Golgi markers. Other intracellular trafficking compartments positive for EEA1 and Rab9A display a modified cellular pattern. In conclusion, lasalocid protects cells from multiple deadly bacterial toxins by corrupting vesicular trafficking and Golgi stack homeostasis. Full article
(This article belongs to the Special Issue Inhibitors and Countermeasures against Bacterial and Plant Toxins)
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Review

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Open AccessReview
Targeting the Early Endosome-to-Golgi Transport of Shiga Toxins as a Therapeutic Strategy
Toxins 2020, 12(5), 342; https://doi.org/10.3390/toxins12050342 - 22 May 2020
Abstract
Shiga toxin (STx) produced by Shigella and closely related Shiga toxin 1 and 2 (STx1 and STx2) synthesized by Shiga toxin-producing Escherichia coli (STEC) are bacterial AB5 toxins. All three toxins target kidney cells and may cause life-threatening renal disease. While Shigella [...] Read more.
Shiga toxin (STx) produced by Shigella and closely related Shiga toxin 1 and 2 (STx1 and STx2) synthesized by Shiga toxin-producing Escherichia coli (STEC) are bacterial AB5 toxins. All three toxins target kidney cells and may cause life-threatening renal disease. While Shigella infections can be treated with antibiotics, resistance is increasing. Moreover, antibiotic therapy is contraindicated for STEC, and there are no definitive treatments for STEC-induced disease. To exert cellular toxicity, STx, STx1, and STx2 must undergo retrograde trafficking to reach their cytosolic target, ribosomes. Direct transport from early endosomes to the Golgi apparatus is an essential step that allows the toxins to bypass degradative late endosomes and lysosomes. The essentiality of this transport step also makes it an ideal target for the development of small-molecule inhibitors of toxin trafficking as potential therapeutics. Here, we review the recent advances in understanding the molecular mechanisms of the early endosome-to-Golgi transport of STx, STx1, and STx2, as well as the development of small-molecule inhibitors of toxin trafficking that act at the endosome/Golgi interface. Full article
(This article belongs to the Special Issue Inhibitors and Countermeasures against Bacterial and Plant Toxins)
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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Title: A Humanized Monoclonal Antibody Cocktail to Prevent Pulmonary Ricin Intoxicatio
Authors: Nicholas J Mantis
Affiliation: Division of Infectious Diseases, Wadsworth Center, New York State Dept. Health
Abstract: PB10 IgG1, a monoclonal antibody (mAb) directed an immunodominant epitope on RT’s enzymatic subunit (RTA), has been shown to passively protect mice and non-human primates from an aerosolized lethal dose ricin toxin (RT) challenge. However, it was recently demonstrated that the therapeutic efficacy of PB10 IgG1 is significantly improved when co-administered with a second mAb, SylH3, targeting RT’s binding subunit (RTB). Here we report that the PB10/SyH3 cocktail is also superior to PB10 alone when used as apre-exposure prophylactic (PrEP) in a mouse model of intranasal RT challenge. The benefit of the PB10/SyH3 cocktail prompted us to engineer a humanized IgG1 version of SylH3 (huSylH3). The huPB10/huSyH3 cocktail proved highly efficacious in the mouse model, thereby opening the door to future testing in non-human primates.

Title: Zaragozic Acid Reduces the Toxic Effect of ETX on MDCK Cells by Disrupting the Lipid Raft
Authors: Jing Huang 1,2, Zhijun Geng 2, Lin Kang 2, Shan Gao 2, Yanwei Li 2, Yuan Yuan 2, Baohua Zhao 1, Jinglin Wang 2, Wenwen Xin 2,
Affiliation: 1 Life Science Institute of Hebei Normal University, Shijiazhuang, China; 2 State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, AMMS, Beijing, China;
Abstract: Epsilon-toxin (ETX) which is produced by types B and D strains of Clostridium perfringens can cause fatal enterotoxaemia in ruminant animals, mainly sheep, cattle and goats. Previous studies showed that cytotoxicity of ETX is dependent upon integrity of lipid raft, and cholesterol plays a vital role in retaining the integrity of lipid raft. Zaragozic acid (ZA) is statin drug that is able to inhibit the activity of β-hydroxy β-methylglutaryl- coenzyme A which is responsible for cholesterol synthesis. In this study, we found that ZA significantly reduces the toxicity of ETX to MDCK cells. Subsequently, we demonstrated that ZA observably affects the binding of ETX to MDCK cells and prevents the toxin-induced Ca2+ influx of the cells binding, respectively. In addition, propidium iodide (PI) staining and western blot also confirmed that ZA also significantly damaged the ability of ETX to form pores or oligomers in MDCK cells. In summary, these findings indicated that ZA is a potential candidate to treat the toxic effects of ETX.

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