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Open AccessArticle

Effect of Vitamin K3 Inhibiting the Function of NorA Efflux Pump and Its Gene Expression on Staphylococcus aureus

1
Laboratory of Microbiology and Molecular Biology (LMBM), Department of Biological Chemistry/CCBS/URCA, Crato 63105-000, Brazil
2
Fiocruz, Departamento de microbiologia, Instituto Aggeu Magalhães , Recife 50740-465, Brazil
3
Laboratory of Microrganism Genetics (LGM), Department of Molecular Biology/CCEN/UFPB; João Pessoa 58051-900, Brazil
4
Laboratory of Natural Products (LPPN), Department of Biological Chemistry/CCBS/URCA, Crato 63105-000, Brazil
5
Department of Chemistry, University of Utah, Salt Lake City, UT 84112, USA
6
Department of Medicinal Chemistry, University of Utah, Salt Lake City, UT 84112, USA
7
Department of Genetics, Federal University of Pernambuco, Recife 50670-901, Brazil
*
Author to whom correspondence should be addressed.
Membranes 2020, 10(6), 130; https://doi.org/10.3390/membranes10060130
Received: 27 May 2020 / Revised: 12 June 2020 / Accepted: 23 June 2020 / Published: 25 June 2020
(This article belongs to the Special Issue Dynamics and Nano-Organization in Plasma Membranes)
Resistance to antibiotics has made diseases that previously healed easily become more difficult to treat. Staphylococcus aureus is an important cause of hospital-acquired infections and multi-drug resistant. NorA efflux pump, present in bacteria S. aureus, is synthesized by the expression of the norA gene. Menadione, also known as vitamin K3, is one of the synthetic forms of vitamin K. Therefore, the aim of this study is to verify the menadione effect on efflux inhibition through NorA pump gene expression inhibition and assess the effects of menadione in bacterial membrane. The effect of menadione as an efflux pump inhibitor (EPI) was evaluated by the microdilution method, fluorimetry, electron microscopy, and by RT-qPCR to evaluate gene expression. In the molecular docking, association with menadione induces increased fluorescence intensity. Menadione was observed (100% of the clusters) interacting with residues ILE12, ILE15, PHE16, ILE19, PHE47, GLN51, ALA105, and MET109 from NorA. The results showed the norA gene had its expression significantly diminished in the presence of menadione. The simulation showed that several menadione molecules were able to go through the bilayer and allow the entry of water molecules into the hydrophobic regions of the bilayer. When present within membranes, menadione may have caused membrane structural changes resulting in a decline of the signaling pathways involved in norA expression. Menadione demonstrated to be an efflux pump inhibitor with dual mechanism: affecting the efflux pump by direct interaction with protein NorA and indirectly inhibiting the norA gene expression, possibly by affecting regulators present in the membrane altered by menadione. View Full-Text
Keywords: efflux pump; ethidium bromide; menadione; NorA; S. aureus efflux pump; ethidium bromide; menadione; NorA; S. aureus
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Tintino, S.R.; Souza, V.C.A.; Silva, J.M.A.; Oliveira-Tintino, C.D.M.; Pereira, P.S.; Leal-Balbino, T.C.; Pereira-Neves, A.; Siqueira-Junior, J.P.; da Costa, J.G.M.; Rodrigues, F.F.G.; Menezes, I.R.A.; da Hora, G.C.A.; Lima, M.C.P.; Coutinho, H.D.M.; Balbino, V.Q. Effect of Vitamin K3 Inhibiting the Function of NorA Efflux Pump and Its Gene Expression on Staphylococcus aureus. Membranes 2020, 10, 130.

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