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Autophagy as a Mechanism for Adaptive Prediction-Mediated Emergence of Drug Resistance

Drug resistance is a major problem in treatment of microbial infections and cancers. There is growing evidence that a transient drug tolerant state may precede and potentiate the emergence of drug resistance. Therefore, understanding the mechanisms leading to tolerance is critical for combating drug...

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Autores principales: Nivedita, Nivedita, Aitchison, John D., Baliga, Nitin S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8461305/
https://www.ncbi.nlm.nih.gov/pubmed/34566920
http://dx.doi.org/10.3389/fmicb.2021.712631
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author Nivedita, Nivedita
Aitchison, John D.
Baliga, Nitin S.
author_facet Nivedita, Nivedita
Aitchison, John D.
Baliga, Nitin S.
author_sort Nivedita, Nivedita
collection PubMed
description Drug resistance is a major problem in treatment of microbial infections and cancers. There is growing evidence that a transient drug tolerant state may precede and potentiate the emergence of drug resistance. Therefore, understanding the mechanisms leading to tolerance is critical for combating drug resistance and for the development of effective therapeutic strategy. Through laboratory evolution of yeast, we recently demonstrated that adaptive prediction (AP), a strategy employed by organisms to anticipate and prepare for a future stressful environment, can emerge within 100 generations by linking the response triggered by a neutral cue (caffeine) to a mechanism of protection against a lethal agent (5-fluoroorotic acid, 5-FOA). Here, we demonstrate that mutations selected across multiple laboratory-evolved lines had linked the neutral cue response to core genes of autophagy. Across these evolved lines, conditional activation of autophagy through AP conferred tolerance, and potentiated subsequent selection of mutations in genes specific to overcoming the toxicity of 5-FOA. These results offer a new perspective on how extensive genome-wide genetic interactions of autophagy could have facilitated the emergence of AP over short evolutionary timescales to potentiate selection of 5-FOA resistance-conferring mutations.
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spelling pubmed-84613052021-09-25 Autophagy as a Mechanism for Adaptive Prediction-Mediated Emergence of Drug Resistance Nivedita, Nivedita Aitchison, John D. Baliga, Nitin S. Front Microbiol Microbiology Drug resistance is a major problem in treatment of microbial infections and cancers. There is growing evidence that a transient drug tolerant state may precede and potentiate the emergence of drug resistance. Therefore, understanding the mechanisms leading to tolerance is critical for combating drug resistance and for the development of effective therapeutic strategy. Through laboratory evolution of yeast, we recently demonstrated that adaptive prediction (AP), a strategy employed by organisms to anticipate and prepare for a future stressful environment, can emerge within 100 generations by linking the response triggered by a neutral cue (caffeine) to a mechanism of protection against a lethal agent (5-fluoroorotic acid, 5-FOA). Here, we demonstrate that mutations selected across multiple laboratory-evolved lines had linked the neutral cue response to core genes of autophagy. Across these evolved lines, conditional activation of autophagy through AP conferred tolerance, and potentiated subsequent selection of mutations in genes specific to overcoming the toxicity of 5-FOA. These results offer a new perspective on how extensive genome-wide genetic interactions of autophagy could have facilitated the emergence of AP over short evolutionary timescales to potentiate selection of 5-FOA resistance-conferring mutations. Frontiers Media S.A. 2021-09-10 /pmc/articles/PMC8461305/ /pubmed/34566920 http://dx.doi.org/10.3389/fmicb.2021.712631 Text en Copyright © 2021 Nivedita, Aitchison and Baliga. 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 Microbiology
Nivedita, Nivedita
Aitchison, John D.
Baliga, Nitin S.
Autophagy as a Mechanism for Adaptive Prediction-Mediated Emergence of Drug Resistance
title Autophagy as a Mechanism for Adaptive Prediction-Mediated Emergence of Drug Resistance
title_full Autophagy as a Mechanism for Adaptive Prediction-Mediated Emergence of Drug Resistance
title_fullStr Autophagy as a Mechanism for Adaptive Prediction-Mediated Emergence of Drug Resistance
title_full_unstemmed Autophagy as a Mechanism for Adaptive Prediction-Mediated Emergence of Drug Resistance
title_short Autophagy as a Mechanism for Adaptive Prediction-Mediated Emergence of Drug Resistance
title_sort autophagy as a mechanism for adaptive prediction-mediated emergence of drug resistance
topic Microbiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8461305/
https://www.ncbi.nlm.nih.gov/pubmed/34566920
http://dx.doi.org/10.3389/fmicb.2021.712631
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