Drug-Driven Phenotypic Convergence Supports Rational Treatment Strategies of Chronic Infections

Lejla Imamovic, Mostafa Mostafa Hashim Ellabaan, Ana Manuel Dantas Machado, Linda Citterio, Tune Wulff, Søren Molin, Helle Krogh Johansen, Morten Otto Alexander Sommer*

*Corresponding author for this work

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Abstract

Chronic Pseudomonas aeruginosa infections evade antibiotic therapy and are associated with mortality in cystic fibrosis (CF) patients. We find that in vitro resistance evolution of P. aeruginosa toward clinically relevant antibiotics leads to phenotypic convergence toward distinct states. These states are associated with collateral sensitivity toward several antibiotic classes and encoded by mutations in antibiotic resistance genes, including transcriptional regulator nfxB. Longitudinal analysis of isolates from CF patients reveals similar and defined phenotypic states, which are associated with extinction of specific sub-lineages in patients. In-depth investigation of chronic P. aeruginosa populations in a CF patient during antibiotic therapy revealed dramatic genotypic and phenotypic convergence. Notably, fluoroquinolone-resistant subpopulations harboring nfxB mutations were eradicated by antibiotic therapy as predicted by our in vitro data. This study supports the hypothesis that antibiotic treatment of chronic infections can be optimized by targeting phenotypic states associated with specific mutations to improve treatment success in chronic infections.
Original languageEnglish
JournalCELL
Volume172
Issue number1-2
Pages (from-to)121-134
ISSN0092-8674
DOIs
Publication statusPublished - 2018

Bibliographical note

Open Access funded by European Research Council
Under a Creative Commons license

Cite this

Imamovic, Lejla ; Ellabaan, Mostafa Mostafa Hashim ; Dantas Machado, Ana Manuel ; Citterio, Linda ; Wulff, Tune ; Molin, Søren ; Johansen, Helle Krogh ; Sommer, Morten Otto Alexander. / Drug-Driven Phenotypic Convergence Supports Rational Treatment Strategies of Chronic Infections. In: CELL. 2018 ; Vol. 172, No. 1-2. pp. 121-134.
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abstract = "Chronic Pseudomonas aeruginosa infections evade antibiotic therapy and are associated with mortality in cystic fibrosis (CF) patients. We find that in vitro resistance evolution of P. aeruginosa toward clinically relevant antibiotics leads to phenotypic convergence toward distinct states. These states are associated with collateral sensitivity toward several antibiotic classes and encoded by mutations in antibiotic resistance genes, including transcriptional regulator nfxB. Longitudinal analysis of isolates from CF patients reveals similar and defined phenotypic states, which are associated with extinction of specific sub-lineages in patients. In-depth investigation of chronic P. aeruginosa populations in a CF patient during antibiotic therapy revealed dramatic genotypic and phenotypic convergence. Notably, fluoroquinolone-resistant subpopulations harboring nfxB mutations were eradicated by antibiotic therapy as predicted by our in vitro data. This study supports the hypothesis that antibiotic treatment of chronic infections can be optimized by targeting phenotypic states associated with specific mutations to improve treatment success in chronic infections.",
author = "Lejla Imamovic and Ellabaan, {Mostafa Mostafa Hashim} and {Dantas Machado}, {Ana Manuel} and Linda Citterio and Tune Wulff and S{\o}ren Molin and Johansen, {Helle Krogh} and Sommer, {Morten Otto Alexander}",
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language = "English",
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pages = "121--134",
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Drug-Driven Phenotypic Convergence Supports Rational Treatment Strategies of Chronic Infections. / Imamovic, Lejla; Ellabaan, Mostafa Mostafa Hashim; Dantas Machado, Ana Manuel; Citterio, Linda; Wulff, Tune; Molin, Søren; Johansen, Helle Krogh; Sommer, Morten Otto Alexander.

In: CELL, Vol. 172, No. 1-2, 2018, p. 121-134.

Research output: Contribution to journalJournal articleResearchpeer-review

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AU - Imamovic, Lejla

AU - Ellabaan, Mostafa Mostafa Hashim

AU - Dantas Machado, Ana Manuel

AU - Citterio, Linda

AU - Wulff, Tune

AU - Molin, Søren

AU - Johansen, Helle Krogh

AU - Sommer, Morten Otto Alexander

N1 - Open Access funded by European Research Council Under a Creative Commons license

PY - 2018

Y1 - 2018

N2 - Chronic Pseudomonas aeruginosa infections evade antibiotic therapy and are associated with mortality in cystic fibrosis (CF) patients. We find that in vitro resistance evolution of P. aeruginosa toward clinically relevant antibiotics leads to phenotypic convergence toward distinct states. These states are associated with collateral sensitivity toward several antibiotic classes and encoded by mutations in antibiotic resistance genes, including transcriptional regulator nfxB. Longitudinal analysis of isolates from CF patients reveals similar and defined phenotypic states, which are associated with extinction of specific sub-lineages in patients. In-depth investigation of chronic P. aeruginosa populations in a CF patient during antibiotic therapy revealed dramatic genotypic and phenotypic convergence. Notably, fluoroquinolone-resistant subpopulations harboring nfxB mutations were eradicated by antibiotic therapy as predicted by our in vitro data. This study supports the hypothesis that antibiotic treatment of chronic infections can be optimized by targeting phenotypic states associated with specific mutations to improve treatment success in chronic infections.

AB - Chronic Pseudomonas aeruginosa infections evade antibiotic therapy and are associated with mortality in cystic fibrosis (CF) patients. We find that in vitro resistance evolution of P. aeruginosa toward clinically relevant antibiotics leads to phenotypic convergence toward distinct states. These states are associated with collateral sensitivity toward several antibiotic classes and encoded by mutations in antibiotic resistance genes, including transcriptional regulator nfxB. Longitudinal analysis of isolates from CF patients reveals similar and defined phenotypic states, which are associated with extinction of specific sub-lineages in patients. In-depth investigation of chronic P. aeruginosa populations in a CF patient during antibiotic therapy revealed dramatic genotypic and phenotypic convergence. Notably, fluoroquinolone-resistant subpopulations harboring nfxB mutations were eradicated by antibiotic therapy as predicted by our in vitro data. This study supports the hypothesis that antibiotic treatment of chronic infections can be optimized by targeting phenotypic states associated with specific mutations to improve treatment success in chronic infections.

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