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Bacterial Protein Homeostasis Disruption as a Therapeutic Intervention

Cells have evolved a complex molecular network, collectively called the protein homeostasis (proteostasis) network, to produce and maintain proteins in the appropriate conformation, concentration and subcellular localization. Loss of proteostasis leads to a reduction in cell viability, which occurs...

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Autores principales: Khodaparast, Laleh, Wu, Guiqin, Khodaparast, Ladan, Schmidt, Béla Z., Rousseau, Frederic, Schymkowitz, Joost
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8206779/
https://www.ncbi.nlm.nih.gov/pubmed/34150852
http://dx.doi.org/10.3389/fmolb.2021.681855
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author Khodaparast, Laleh
Wu, Guiqin
Khodaparast, Ladan
Schmidt, Béla Z.
Rousseau, Frederic
Schymkowitz, Joost
author_facet Khodaparast, Laleh
Wu, Guiqin
Khodaparast, Ladan
Schmidt, Béla Z.
Rousseau, Frederic
Schymkowitz, Joost
author_sort Khodaparast, Laleh
collection PubMed
description Cells have evolved a complex molecular network, collectively called the protein homeostasis (proteostasis) network, to produce and maintain proteins in the appropriate conformation, concentration and subcellular localization. Loss of proteostasis leads to a reduction in cell viability, which occurs to some degree during healthy ageing, but is also the root cause of a group of diverse human pathologies. The accumulation of proteins in aberrant conformations and their aggregation into specific beta-rich assemblies are particularly detrimental to cell viability and challenging to the protein homeostasis network. This is especially true for bacteria; it can be argued that the need to adapt to their changing environments and their high protein turnover rates render bacteria particularly vulnerable to the disruption of protein homeostasis in general, as well as protein misfolding and aggregation. Targeting bacterial proteostasis could therefore be an attractive strategy for the development of novel antibacterial therapeutics. This review highlights advances with an antibacterial strategy that is based on deliberately inducing aggregation of target proteins in bacterial cells aiming to induce a lethal collapse of protein homeostasis. The approach exploits the intrinsic aggregation propensity of regions residing in the hydrophobic core regions of the polypeptide sequence of proteins, which are genetically conserved because of their essential role in protein folding and stability. Moreover, the molecules were designed to target multiple proteins, to slow down the build-up of resistance. Although more research is required, results thus far allow the hope that this strategy may one day contribute to the arsenal to combat multidrug-resistant bacterial infections.
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spelling pubmed-82067792021-06-17 Bacterial Protein Homeostasis Disruption as a Therapeutic Intervention Khodaparast, Laleh Wu, Guiqin Khodaparast, Ladan Schmidt, Béla Z. Rousseau, Frederic Schymkowitz, Joost Front Mol Biosci Molecular Biosciences Cells have evolved a complex molecular network, collectively called the protein homeostasis (proteostasis) network, to produce and maintain proteins in the appropriate conformation, concentration and subcellular localization. Loss of proteostasis leads to a reduction in cell viability, which occurs to some degree during healthy ageing, but is also the root cause of a group of diverse human pathologies. The accumulation of proteins in aberrant conformations and their aggregation into specific beta-rich assemblies are particularly detrimental to cell viability and challenging to the protein homeostasis network. This is especially true for bacteria; it can be argued that the need to adapt to their changing environments and their high protein turnover rates render bacteria particularly vulnerable to the disruption of protein homeostasis in general, as well as protein misfolding and aggregation. Targeting bacterial proteostasis could therefore be an attractive strategy for the development of novel antibacterial therapeutics. This review highlights advances with an antibacterial strategy that is based on deliberately inducing aggregation of target proteins in bacterial cells aiming to induce a lethal collapse of protein homeostasis. The approach exploits the intrinsic aggregation propensity of regions residing in the hydrophobic core regions of the polypeptide sequence of proteins, which are genetically conserved because of their essential role in protein folding and stability. Moreover, the molecules were designed to target multiple proteins, to slow down the build-up of resistance. Although more research is required, results thus far allow the hope that this strategy may one day contribute to the arsenal to combat multidrug-resistant bacterial infections. Frontiers Media S.A. 2021-06-02 /pmc/articles/PMC8206779/ /pubmed/34150852 http://dx.doi.org/10.3389/fmolb.2021.681855 Text en Copyright © 2021 Khodaparast, Wu, Khodaparast, Schmidt, Rousseau and Schymkowitz. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Molecular Biosciences
Khodaparast, Laleh
Wu, Guiqin
Khodaparast, Ladan
Schmidt, Béla Z.
Rousseau, Frederic
Schymkowitz, Joost
Bacterial Protein Homeostasis Disruption as a Therapeutic Intervention
title Bacterial Protein Homeostasis Disruption as a Therapeutic Intervention
title_full Bacterial Protein Homeostasis Disruption as a Therapeutic Intervention
title_fullStr Bacterial Protein Homeostasis Disruption as a Therapeutic Intervention
title_full_unstemmed Bacterial Protein Homeostasis Disruption as a Therapeutic Intervention
title_short Bacterial Protein Homeostasis Disruption as a Therapeutic Intervention
title_sort bacterial protein homeostasis disruption as a therapeutic intervention
topic Molecular Biosciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8206779/
https://www.ncbi.nlm.nih.gov/pubmed/34150852
http://dx.doi.org/10.3389/fmolb.2021.681855
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