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Vitamin E Increases Antimicrobial Sensitivity by Inhibiting Bacterial Lipocalin Antibiotic Binding.
- Source :
-
MSphere [mSphere] 2018 Dec 12; Vol. 3 (6). Date of Electronic Publication: 2018 Dec 12. - Publication Year :
- 2018
-
Abstract
- Burkholderia cenocepacia is an opportunistic Gram-negative bacterium that causes serious respiratory infections in patients with cystic fibrosis. Recently, we discovered that B. cenocepacia produces the extracellular bacterial lipocalin protein BcnA upon exposure to sublethal concentrations of bactericidal antibiotics. BcnA captures a range of antibiotics outside bacterial cells, providing a global extracellular mechanism of antimicrobial resistance. In this study, we investigated water-soluble and liposoluble forms of vitamin E as inhibitors of antibiotic binding by BcnA. Our results demonstrate that in vitro , both vitamin E forms bind strongly to BcnA and contribute to reduce the MICs of norfloxacin (a fluoroquinolone) and ceftazidime (a β-lactam), both of them used as model molecules representing two different chemical classes of antibiotics. Expression of BcnA was required for the adjuvant effect of vitamin E. These results were replicated in vivo using the Galleria mellonella larva infection model whereby vitamin E treatment, in combination with norfloxacin, significantly increased larva survival upon infection in a BcnA-dependent manner. Together, our data suggest that vitamin E can be used to increase killing by bactericidal antibiotics through interference with lipocalin binding. IMPORTANCE Bacteria exposed to stress mediated by sublethal antibiotic concentrations respond by adaptive mechanisms leading to an overall increase of antibiotic resistance. One of these mechanisms involves the release of bacterial proteins called lipocalins, which have the ability to sequester antibiotics in the extracellular space before they reach bacterial cells. We speculated that interfering with lipocalin-mediated antibiotic binding could enhance the efficacy of antibiotics to kill bacteria. In this work, we report that when combined with bactericidal antibiotics, vitamin E contributes to enhance bacterial killing both in vitro and in vivo. This adjuvant effect of vitamin E requires the presence of BcnA, a bacterial lipocalin produced by the cystic fibrosis pathogen Burkholderia cenocepacia Since most bacteria produce lipocalins like BcnA, we propose that our findings could be translated into making novel antibiotic adjuvants to potentiate bacterial killing by existing antibiotics.<br /> (Copyright © 2018 Naguib and Valvano.)
- Subjects :
- Animals
Anti-Bacterial Agents metabolism
Burkholderia Infections drug therapy
Burkholderia Infections microbiology
Burkholderia cenocepacia drug effects
Ceftazidime administration & dosage
Ceftazidime metabolism
Disease Models, Animal
Drug Therapy, Combination methods
Larva microbiology
Larva physiology
Lepidoptera microbiology
Lepidoptera physiology
Microbial Sensitivity Tests
Norfloxacin administration & dosage
Norfloxacin metabolism
Survival Analysis
Vitamin E administration & dosage
Anti-Bacterial Agents pharmacology
Bacterial Proteins antagonists & inhibitors
Burkholderia cenocepacia metabolism
Ceftazidime pharmacology
Lipocalins antagonists & inhibitors
Norfloxacin pharmacology
Vitamin E metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2379-5042
- Volume :
- 3
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- MSphere
- Publication Type :
- Academic Journal
- Accession number :
- 30541778
- Full Text :
- https://doi.org/10.1128/mSphere.00564-18