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

TY - JOUR

T1 - Drug-Driven Phenotypic Convergence Supports Rational Treatment Strategies of Chronic Infections

AU - Imamovic, Lejla

AU - Ellabaan, Mostafa Mostafa Hashim

AU - Dantas Machado, Ana Manuel

AU - Citterio, Linda

AU - Wulff, Tune

AU - Molin, Soren

AU - Krogh Johansen, Helle

AU - Sommer, Morten Otto Alexander

N1 - Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

PY - 2018/1/11

Y1 - 2018/1/11

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. The evolution of antibiotic resistance of Pseudomonas infection in cystic fibrosis patients confers predictable sensitivities to other classes of antibiotics, suggesting new ways to optimize treatments for chronic infection.

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. The evolution of antibiotic resistance of Pseudomonas infection in cystic fibrosis patients confers predictable sensitivities to other classes of antibiotics, suggesting new ways to optimize treatments for chronic infection.

KW - Anti-Bacterial Agents/pharmacology

KW - Bacterial Proteins/genetics

KW - Cystic Fibrosis/complications

KW - DNA-Binding Proteins/genetics

KW - Drug Resistance, Bacterial

KW - Evolution, Molecular

KW - Humans

KW - Male

KW - Middle Aged

KW - Mutation

KW - Phenotype

KW - Pseudomonas Infections/complications

KW - Pseudomonas aeruginosa/drug effects

KW - Selection, Genetic

KW - Transcription Factors/genetics

U2 - 10.1016/j.cell.2017.12.012

DO - 10.1016/j.cell.2017.12.012

M3 - Journal article

C2 - 29307490

SN - 0092-8674

VL - 172

SP - 121-134.e14

JO - Cell

JF - Cell

IS - 1-2

ER -