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Inhibition of Staphylococcus aureus TetK and MsrA efflux pumps by hydroxyamines derived from lapachol and norlachol

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Abstract

The present study aimed to evaluate the in vitro efflux pump inhibitory capacity of hydroxyamines derived from lapachol and norlachol, where compounds 3, 4, and 5 were tested against the S. aureus strains: RN4220 carrying the pUL5054 plasmid; and IS-58, endowed with the PT181 plasmid. The substances were synthesized from 2-hydroxy-quinones, lapachol and nor-lapachol obtaining the corresponding 2-methoxylated derivatives via dimethyl sulfate alkylation in a basic medium, which then reacted chemoselectively with 2-ethanolamine and 3-propanolamine to form the corresponding amino alcohols. The antibacterial action of the substances was quantified by determining the Minimum Inhibitory Concentration (MIC), while a microdilution assay was carried out to ascertain efflux pump inhibition of Staphylococcus aureus strains carrying the MsrA macrolide and the TetK tetracycline efflux pumps with the substances at a sub-inhibitory concentration. The results were subjected to statistical analysis by an ANOVA test and Bonferroni post hoc test. The MIC from the substances exhibited a value ≥ 1024 µg/mL. However, a significant reduction (p < 0.0001) of the erythromycin, tetracycline and ethidium bromide MIC was demonstrated when these were in combination with the substances, with this effect being due to a supposed efflux pump inhibition. The tested substances demonstrated effectiveness at decreasing the MIC of erythromycin, tetracycline and ethidium bromide, potentially by inhibiting the MsrA macrolide and the TetK tetracycline efflux pumps present in the tested S. aureus strains.

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Authors and Affiliations

  1. Postgraduate Program in Development and Technological Innovation in Medicines, Federal University of Ceará, Fortaleza, CEP 60.430-370, CE, Brazil

    Fernando Gomes Figueredo & Marta Maria de Franca Fonteles

  2. Department of Microbiology, Faculdade de Medicina Estácio de Juazeiro do Norte, Juazeiro do Norte- CE, Juazeiro do Norte, CEP 63048-080, CE, Brazil

    Fernando Gomes Figueredo, Rodrigo Emmanuel L. T. Parente, Maynara Rodrigues Cavalcante-Figueredo, Jakson Gomes Figueiredo & Edinardo Fagner Ferreira Matias

  3. Department of Biological Chemistry, Regional University of Cariri, Crato, CEP 63105-000, CE, Brazil

    Raimundo Luiz Pereira da Silva, Cícera Datiane de Morais Oliveira-Tintino, Saulo Relison Tintino & Henrique Douglas Melo Coutinho

  4. Department of Chemistry, Universidade Federal Rural de Pernambuco, Recife, PE, Brazil

    Tania Maria Sarmento Silva & Celso Amorim Camara

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  1. Fernando Gomes Figueredo
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Correspondence to Henrique Douglas Melo Coutinho.

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Figueredo, F.G., Parente, R.E.L.T., Cavalcante-Figueredo, M.R. et al. Inhibition of Staphylococcus aureus TetK and MsrA efflux pumps by hydroxyamines derived from lapachol and norlachol. J Bioenerg Biomembr 53, 149–156 (2021). https://doi.org/10.1007/s10863-021-09885-5

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