Drug-driven phenotypic convergence supports rational treatment strategies of chronic infections

ABSTRACT: Chronic Pseudomonas aeruginosa infections evades antibiotic therapy and are associated with mortality in cystic fibrosis (CF) patients. We find that in vitro resistance evolution of P.aeruginosa towards clinically relevant antibiotics leads to phenotypic convergence towards distinct states. These states are associated with collateral sensitivity towards 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.

INSTRUMENT(S): Synapt MS

ORGANISM(S): Pseudomonas Aeruginosa Pao1

TISSUE(S): Permanent Cell Line Cell, Cell Culture

DISEASE(S): Cystic Fibrosis

SUBMITTER: Tune Wulff  

LAB HEAD: Morten Otto Alexander Sommer

PROVIDER: PXD007972 | Pride | 2018-10-23

REPOSITORIES: Pride