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The ionophore oxyclozanide enhances tobramycin killing of Pseudomonas aeruginosa biofilms by permeabilizing cells and depolarizing the membrane potential
- Source :
- Journal of Antimicrobial Chemotherapy. 74:894-906
- Publication Year :
- 2019
- Publisher :
- Oxford University Press (OUP), 2019.
-
Abstract
- ObjectivesTo assess the ability of oxyclozanide to enhance tobramycin killing of Pseudomonas aeruginosa biofilms and elucidate its mechanism of action.MethodsTwenty-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.ResultsHere 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.ConclusionsOxyclozanide 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.
- Subjects :
- 0301 basic medicine
Microbiology (medical)
medicine.drug_class
Tetracycline
030106 microbiology
Antibiotics
Oxyclozanide
medicine.disease_cause
Permeability
Membrane Potentials
Microbiology
03 medical and health sciences
chemistry.chemical_compound
medicine
Tobramycin
Humans
Pseudomonas Infections
Pharmacology (medical)
Child
Original Research
Pharmacology
Antiinfective agent
Microbial Viability
Pseudomonas aeruginosa
Cell Membrane
Aminoglycoside
Biofilm
Infant
Drug Synergism
biochemical phenomena, metabolism, and nutrition
Anti-Bacterial Agents
030104 developmental biology
Infectious Diseases
chemistry
Biofilms
medicine.drug
Subjects
Details
- ISSN :
- 14602091 and 03057453
- Volume :
- 74
- Database :
- OpenAIRE
- Journal :
- Journal of Antimicrobial Chemotherapy
- Accession number :
- edsair.doi.dedup.....d5953a68c07443be3f95973adbc9f98c