Evaluation of combination therapy for Burkholderia cenocepacia lung infection in different in vitro and in vivo models

PLoS One. 2017 Mar 1;12(3):e0172723. doi: 10.1371/journal.pone.0172723. eCollection 2017.

Abstract

Burkholderia cenocepacia is an opportunistic pathogen responsible for life-threatening infections in cystic fibrosis patients. B. cenocepacia is extremely resistant towards antibiotics and therapy is complicated by its ability to form biofilms. We investigated the efficacy of an alternative antimicrobial strategy for B. cenocepacia lung infections using in vitro and in vivo models. A screening of the NIH Clinical Collection 1&2 was performed against B. cenocepacia biofilms formed in 96-well microtiter plates in the presence of tobramycin to identify repurposing candidates with potentiator activity. The efficacy of selected hits was evaluated in a three-dimensional (3D) organotypic human lung epithelial cell culture model. The in vivo effect was evaluated in the invertebrate Galleria mellonella and in a murine B. cenocepacia lung infection model. The screening resulted in 60 hits that potentiated the activity of tobramycin against B. cenocepacia biofilms, including four imidazoles of which econazole and miconazole were selected for further investigation. However, a potentiator effect was not observed in the 3D organotypic human lung epithelial cell culture model. Combination treatment was also not able to increase survival of infected G. mellonella. Also in mice, there was no added value for the combination treatment. Although potentiators of tobramycin with activity against biofilms of B. cenocepacia were identified in a repurposing screen, the in vitro activity could not be confirmed nor in a more sophisticated in vitro model, neither in vivo. This stresses the importance of validating hits resulting from in vitro studies in physiologically relevant model systems.

MeSH terms

  • A549 Cells
  • Animals
  • Biofilms / drug effects*
  • Biofilms / growth & development
  • Burkholderia Infections / drug therapy*
  • Burkholderia Infections / metabolism
  • Burkholderia Infections / pathology
  • Burkholderia cenocepacia / physiology*
  • Disease Models, Animal
  • Drug Evaluation, Preclinical
  • Drug Therapy, Combination / methods
  • Econazole / pharmacology*
  • Female
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Miconazole / pharmacology*
  • Pneumonia, Bacterial / drug therapy*
  • Pneumonia, Bacterial / metabolism
  • Pneumonia, Bacterial / pathology
  • Tobramycin / pharmacology*

Substances

  • Econazole
  • Miconazole
  • Tobramycin

Grants and funding

This work was funded by the Institute for the Promotion of Innovation through Science and Technology in Flanders (IWT-Vlaanderen, SBO programme) (grant no. 12005) and by the Research Foundation Flanders (Odysseus grant). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.