Journal article
Drug-Driven Phenotypic Convergence Supports Rational Treatment Strategies of Chronic Infections
Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark1
Copenhagen University Hospital Herlev and Gentofte2
Research Groups, Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark3
Bacterial Synthetic Biology, Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark4
Department of Systems Biology, Technical University of Denmark5
Department of Biotechnology and Biomedicine, Technical University of Denmark6
Office for Study Programmes and Student Affairs, Administration, Technical University of Denmark7
CHO Core, Translational Management, Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark8
iLoop, Translational Management, Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark9
Infection Microbiology, Research Groups, Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark10
...and 0 moreChronic 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.
| Language: | English |
|---|---|
| Publisher: | Cell Press |
| Year: | 2018 |
| Pages: | 121-134 |
| ISSN: | 10974172 and 00928674 |
| Types: | Journal article |
| DOI: | 10.1016/j.cell.2017.12.012 |
| ORCIDs: | Imamovic, Lejla , Ellabaan, Mostafa Mostafa Hashim , Wulff, Tune , Molin, Søren and Sommer, Morten Otto Alexander |
Anti-Bacterial Agents Anti-Bacterial Agents/pharmacology Bacterial Proteins Bacterial Proteins/genetics Cystic Fibrosis Cystic Fibrosis/complications DNA-Binding Proteins DNA-Binding Proteins/genetics Drug Resistance, Bacterial Evolution, Molecular Humans Male Middle Aged Mutation NfxB protein, Pseudomonas aeruginosa Phenotype Pseudomonas Infections Pseudomonas Infections/complications Pseudomonas aeruginosa Pseudomonas aeruginosa/drug effects Selection, Genetic Transcription Factors Transcription Factors/genetics antibiotic treatment chronic infections collateral sensitivity cystic fibrosis drug resistance nfxB phenotypic convergence
