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 -