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The ionophore oxyclozanide enhances tobramycin killing of Pseudomonas aeruginosa biofilms by permeabilizing cells and depolarizing the membrane potential.
- Source :
-
The Journal of antimicrobial chemotherapy [J Antimicrob Chemother] 2019 Apr 01; Vol. 74 (4), pp. 894-906. - Publication Year :
- 2019
-
Abstract
- Objectives: To assess the ability of oxyclozanide to enhance tobramycin killing of Pseudomonas aeruginosa biofilms and elucidate its mechanism of action.<br />Methods: Twenty-four hour biofilms formed by the P. aeruginosa strain PAO1 and cystic fibrosis (CF) isolates were tested for susceptibility to oxyclozanide and tobramycin killing using BacTiter-Glo™ and cfu. Biofilm dispersal was measured using crystal violet staining. Membrane potential and permeabilization were quantified using DiOC2(3) and TO-PRO-3, respectively.<br />Results: Here we show that the ionophore anthelmintic oxyclozanide, combined with tobramycin, significantly increased killing of P. aeruginosa biofilms over each treatment alone. This combination also significantly accelerated the killing of cells within biofilms and stationary phase cultures and it was effective against 4/6 CF clinical isolates tested, including a tobramycin-resistant strain. Oxyclozanide enhanced the ability of additional aminoglycosides and tetracycline to kill P. aeruginosa biofilms. Finally, oxyclozanide permeabilized cells within the biofilm, reduced the membrane potential and increased tobramycin accumulation within cells of mature P. aeruginosa biofilms.<br />Conclusions: Oxyclozanide enhances aminoglycoside and tetracycline activity against P. aeruginosa biofilms by reducing membrane potential, permeabilizing cells and enhancing tobramycin accumulation within biofilms. We propose that oxyclozanide counteracts the adaptive resistance response of P. aeruginosa to aminoglycosides, increasing both their maximum activity and rate of killing. As oxyclozanide is widely used in veterinary medicine for the treatment of parasitic worm infections, this combination could offer a new approach for the treatment of biofilm-based P. aeruginosa infections, repurposing oxyclozanide as an anti-biofilm agent.<br /> (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
- Subjects :
- Cell Membrane drug effects
Child
Humans
Infant
Membrane Potentials drug effects
Permeability drug effects
Pseudomonas Infections microbiology
Pseudomonas aeruginosa isolation & purification
Anti-Bacterial Agents pharmacology
Biofilms drug effects
Drug Synergism
Microbial Viability drug effects
Oxyclozanide pharmacology
Pseudomonas aeruginosa drug effects
Tobramycin pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1460-2091
- Volume :
- 74
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- The Journal of antimicrobial chemotherapy
- Publication Type :
- Academic Journal
- Accession number :
- 30624737
- Full Text :
- https://doi.org/10.1093/jac/dky545