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Development of Anti-Virulence Therapeutics against Mono-ADP-Ribosyltransferase Toxins

Mono-ADP-ribosyltransferase toxins are often key virulence factors produced by pathogenic bacteria as tools to compromise the target host cell. These toxins are enzymes that use host cellular NAD(+) as the substrate to modify a critical macromolecule target in the host cell machinery. This post-tran...

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Detalles Bibliográficos
Autores principales: Lugo, Miguel R., Merrill, Allan R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7824265/
https://www.ncbi.nlm.nih.gov/pubmed/33375750
http://dx.doi.org/10.3390/toxins13010016
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author Lugo, Miguel R.
Merrill, Allan R.
author_facet Lugo, Miguel R.
Merrill, Allan R.
author_sort Lugo, Miguel R.
collection PubMed
description Mono-ADP-ribosyltransferase toxins are often key virulence factors produced by pathogenic bacteria as tools to compromise the target host cell. These toxins are enzymes that use host cellular NAD(+) as the substrate to modify a critical macromolecule target in the host cell machinery. This post-translational modification of the target macromolecule (usually protein or DNA) acts like a switch to turn the target activity on or off resulting in impairment of a critical process or pathway in the host. One approach to stymie bacterial pathogens is to curtail the toxic action of these factors by designing small molecules that bind tightly to the enzyme active site and prevent catalytic function. The inactivation of these toxins/enzymes is targeted for the site of action within the host cell and small molecule therapeutics can function as anti-virulence agents by disarming the pathogen. This represents an alternative strategy to antibiotic therapy with the potential as a paradigm shift that may circumvent multi-drug resistance in the offending microbe. In this review, work that has been accomplished during the past two decades on this approach to develop anti-virulence compounds against mono-ADP-ribosyltransferase toxins will be discussed.
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spelling pubmed-78242652021-01-24 Development of Anti-Virulence Therapeutics against Mono-ADP-Ribosyltransferase Toxins Lugo, Miguel R. Merrill, Allan R. Toxins (Basel) Review Mono-ADP-ribosyltransferase toxins are often key virulence factors produced by pathogenic bacteria as tools to compromise the target host cell. These toxins are enzymes that use host cellular NAD(+) as the substrate to modify a critical macromolecule target in the host cell machinery. This post-translational modification of the target macromolecule (usually protein or DNA) acts like a switch to turn the target activity on or off resulting in impairment of a critical process or pathway in the host. One approach to stymie bacterial pathogens is to curtail the toxic action of these factors by designing small molecules that bind tightly to the enzyme active site and prevent catalytic function. The inactivation of these toxins/enzymes is targeted for the site of action within the host cell and small molecule therapeutics can function as anti-virulence agents by disarming the pathogen. This represents an alternative strategy to antibiotic therapy with the potential as a paradigm shift that may circumvent multi-drug resistance in the offending microbe. In this review, work that has been accomplished during the past two decades on this approach to develop anti-virulence compounds against mono-ADP-ribosyltransferase toxins will be discussed. MDPI 2020-12-25 /pmc/articles/PMC7824265/ /pubmed/33375750 http://dx.doi.org/10.3390/toxins13010016 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Lugo, Miguel R.
Merrill, Allan R.
Development of Anti-Virulence Therapeutics against Mono-ADP-Ribosyltransferase Toxins
title Development of Anti-Virulence Therapeutics against Mono-ADP-Ribosyltransferase Toxins
title_full Development of Anti-Virulence Therapeutics against Mono-ADP-Ribosyltransferase Toxins
title_fullStr Development of Anti-Virulence Therapeutics against Mono-ADP-Ribosyltransferase Toxins
title_full_unstemmed Development of Anti-Virulence Therapeutics against Mono-ADP-Ribosyltransferase Toxins
title_short Development of Anti-Virulence Therapeutics against Mono-ADP-Ribosyltransferase Toxins
title_sort development of anti-virulence therapeutics against mono-adp-ribosyltransferase toxins
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7824265/
https://www.ncbi.nlm.nih.gov/pubmed/33375750
http://dx.doi.org/10.3390/toxins13010016
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