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, 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.
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
EP - 134
JO - Cell
JF - Cell
IS - 1-2
ER -