Vitamin E Increases Antimicrobial Sensitivity by Inhibiting Bacterial Lipocalin Antibiotic Binding

Abstract

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.

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“…Furthermore, they demonstrated that increased mortality was due to the vitamin E derivative interference with lipocalin binding. Moreover, similar results have been obtained with the same combination against P. aeruginosa PAO1 infection [53].…”

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“…When compared to the norfloxacin-or TPGS-only treatment regimens, the survival of BcnA-producing B. cenocepacia K56-2-infected larvae increased to more than 80% upon treatment with norfloxacin in combination with TPGS. A similar experiment was conducted with P. aeruginosa PAO1-infected larvae also resulting in a significant increase of the larvae survival rate when treated with norfloxacin and TPGS together compared to exclusive norfloxacin application [62].…”

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“…This suggests that sugE was likely learnt to be predictive purely due to its colocation/linkage instead of due to any specific antimicrobial resistance-related function. The presence of this adjacent blc may further potentiate the resistance, as these have been reported in other bacteria to increase MICs of β-lactam antibiotics by binding the antibiotic in the medium (56, 57).…”