Extreme Antibiotic Persistence via Heterogeneity-Generating Mutations Targeting Translation

ABSTRACT Antibiotic persistence, the noninherited tolerance of a subpopulation of bacteria to high levels of antibiotics, is a bet-hedging phenomenon with broad clinical implications. Indeed, the isolation of bacteria with substantially increased persistence rates from chronic infections suggests th...

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Autores principales:	Anupama Khare, Saeed Tavazoie
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	Escherichia coli antibiotic persistence gene expression heterogeneity laboratory evolution persisters systems biology Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/3259ae76ebf443869fd1673943ed5932
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spelling	oai:doaj.org-article:3259ae76ebf443869fd1673943ed59322021-12-02T18:44:38ZExtreme Antibiotic Persistence via Heterogeneity-Generating Mutations Targeting Translation10.1128/mSystems.00847-192379-5077https://doaj.org/article/3259ae76ebf443869fd1673943ed59322020-02-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSystems.00847-19https://doaj.org/toc/2379-5077ABSTRACT Antibiotic persistence, the noninherited tolerance of a subpopulation of bacteria to high levels of antibiotics, is a bet-hedging phenomenon with broad clinical implications. Indeed, the isolation of bacteria with substantially increased persistence rates from chronic infections suggests that evolution of hyperpersistence is a significant factor in clinical therapy resistance. However, the pathways that lead to hyperpersistence and the underlying cellular states have yet to be systematically studied. Here, we show that laboratory evolution can lead to increase in persistence rates by orders of magnitude for multiple independently evolved populations of Escherichia coli and that the driving mutations are highly enriched in translation-related genes. Furthermore, two distinct adaptive mutations converge on concordant transcriptional changes, including increased population heterogeneity in the expression of several genes. Cells with extreme expression of these genes showed dramatic differences in persistence rates, enabling isolation of subpopulations in which a substantial fraction of cells are persisters. Expression analysis reveals coherent regulation of specific pathways that may be critical to establishing the hyperpersistence state. Hyperpersister mutants can thus enable the systematic molecular characterization of this unique physiological state, a critical prerequisite for developing antipersistence strategies. IMPORTANCE Bacterial persistence is a fascinating phenomenon in which a small subpopulation of bacteria becomes phenotypically tolerant to lethal antibiotic exposure. There is growing evidence that populations of bacteria in chronic clinical infections develop a hyperpersistent phenotype, enabling a substantially larger subpopulation to survive repeated antibiotic treatment. The mechanisms of persistence and modes of increasing persistence rates remain largely unknown. Here, we utilized experimental evolution to select for Escherichia coli mutants that have more than a thousandfold increase in persistence rates. We discovered that a variety of individual mutations to translation-related processes are causally involved. Furthermore, we found that these mutations lead to population heterogeneity in the expression of specific genes. We show that this can be used to isolate populations in which the majority of bacteria are persisters, thereby enabling systems-level characterization of this fascinating and clinically significant microbial phenomenon.Anupama KhareSaeed TavazoieAmerican Society for MicrobiologyarticleEscherichia coliantibiotic persistencegene expression heterogeneitylaboratory evolutionpersisterssystems biologyMicrobiologyQR1-502ENmSystems, Vol 5, Iss 1 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Escherichia coli antibiotic persistence gene expression heterogeneity laboratory evolution persisters systems biology Microbiology QR1-502
spellingShingle	Escherichia coli antibiotic persistence gene expression heterogeneity laboratory evolution persisters systems biology Microbiology QR1-502 Anupama Khare Saeed Tavazoie Extreme Antibiotic Persistence via Heterogeneity-Generating Mutations Targeting Translation
description	ABSTRACT Antibiotic persistence, the noninherited tolerance of a subpopulation of bacteria to high levels of antibiotics, is a bet-hedging phenomenon with broad clinical implications. Indeed, the isolation of bacteria with substantially increased persistence rates from chronic infections suggests that evolution of hyperpersistence is a significant factor in clinical therapy resistance. However, the pathways that lead to hyperpersistence and the underlying cellular states have yet to be systematically studied. Here, we show that laboratory evolution can lead to increase in persistence rates by orders of magnitude for multiple independently evolved populations of Escherichia coli and that the driving mutations are highly enriched in translation-related genes. Furthermore, two distinct adaptive mutations converge on concordant transcriptional changes, including increased population heterogeneity in the expression of several genes. Cells with extreme expression of these genes showed dramatic differences in persistence rates, enabling isolation of subpopulations in which a substantial fraction of cells are persisters. Expression analysis reveals coherent regulation of specific pathways that may be critical to establishing the hyperpersistence state. Hyperpersister mutants can thus enable the systematic molecular characterization of this unique physiological state, a critical prerequisite for developing antipersistence strategies. IMPORTANCE Bacterial persistence is a fascinating phenomenon in which a small subpopulation of bacteria becomes phenotypically tolerant to lethal antibiotic exposure. There is growing evidence that populations of bacteria in chronic clinical infections develop a hyperpersistent phenotype, enabling a substantially larger subpopulation to survive repeated antibiotic treatment. The mechanisms of persistence and modes of increasing persistence rates remain largely unknown. Here, we utilized experimental evolution to select for Escherichia coli mutants that have more than a thousandfold increase in persistence rates. We discovered that a variety of individual mutations to translation-related processes are causally involved. Furthermore, we found that these mutations lead to population heterogeneity in the expression of specific genes. We show that this can be used to isolate populations in which the majority of bacteria are persisters, thereby enabling systems-level characterization of this fascinating and clinically significant microbial phenomenon.
format	article
author	Anupama Khare Saeed Tavazoie
author_facet	Anupama Khare Saeed Tavazoie
author_sort	Anupama Khare
title	Extreme Antibiotic Persistence via Heterogeneity-Generating Mutations Targeting Translation
title_short	Extreme Antibiotic Persistence via Heterogeneity-Generating Mutations Targeting Translation
title_full	Extreme Antibiotic Persistence via Heterogeneity-Generating Mutations Targeting Translation
title_fullStr	Extreme Antibiotic Persistence via Heterogeneity-Generating Mutations Targeting Translation
title_full_unstemmed	Extreme Antibiotic Persistence via Heterogeneity-Generating Mutations Targeting Translation
title_sort	extreme antibiotic persistence via heterogeneity-generating mutations targeting translation
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/3259ae76ebf443869fd1673943ed5932
work_keys_str_mv	AT anupamakhare extremeantibioticpersistenceviaheterogeneitygeneratingmutationstargetingtranslation AT saeedtavazoie extremeantibioticpersistenceviaheterogeneitygeneratingmutationstargetingtranslation
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Extreme Antibiotic Persistence via Heterogeneity-Generating Mutations Targeting Translation

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