Menezes Dantas Debora de, Macêdo Nair Silva, Sousa Silveira Zildene de, Santos Barbosa Cristina Rodrigues Dos, Muniz Débora Feitosa, Bezerra Antônio Henrique, Sousa Josivânia Teixeira de, Alencar Gabriel Gonçalves, Morais Oliveira-Tintino Cícera Datiane de, Tintino Saulo Relison, da Rocha Matheus Nunes, Marinho Emmanuel Silva, Marinho Márcia Machado, Dos Santos Hélcio Silva, Melo Coutinho Henrique Douglas, Cunha Francisco Assis Bezerra da
Postgraduate Program in Biological Chemistry, Department of Biological Chemistry, Regional University of Cariri - URCA, Crato, CE, Brazil; Semi-arid Bioprospecting Laboratory and Alternative Methods, Pimenta Campus, Regional University of Cariri - URCA, Crato, CE, Brazil.
Postgraduate Program in Biological Chemistry, Department of Biological Chemistry, Regional University of Cariri - URCA, Crato, CE, Brazil; Semi-arid Bioprospecting Laboratory and Alternative Methods, Pimenta Campus, Regional University of Cariri - URCA, Crato, CE, Brazil.
Microb Pathog. 2025 Jun;203:107504. doi: 10.1016/j.micpath.2025.107504. Epub 2025 Mar 26.
Bacterial resistance is a major challenge in the treatment of Staphylococcus aureus infections, with efflux mechanisms highlighted as reducing the efficacy of antibiotics. In this study, we investigated the potential of naringenin, a natural flavonoid, as an antibacterial agent and efflux pump inhibitor in S. aureus strains 1199 and 1199B. The studies used minimum inhibitory concentration (MIC) assays, ethidium bromide (EtBr) fluorescence emission enhancement assays, cell membrane permeability assays, and in silico molecular docking and ADME prediction assays. Naringenin showed no relevant antibacterial activity (MIC ≥1024 μg/mL). However, it potentiated the effect of norfloxacin and EtBr, reducing their MICs and increasing the fluorescence emission of EtBr, suggesting a possible inhibition of the NorA efflux pump. Bacterial membrane permeability was not significantly affected. Molecular docking assays indicated that naringenin interacts with the chlorpromazine binding site and has more favorable affinity energy than the chlorpromazine-NorA complex. ADME prediction showed favorable physicochemical properties, good oral absorption, metabolic stability and central nervous system safety. Therefore, naringenin demonstrates the potential to reverse the efficacy of norfloxacin in S. aureus by associating with efflux inhibition through effective interactions with the NorA protein, suggesting its therapeutic potential against bacterial resistance.
细菌耐药性是金黄色葡萄球菌感染治疗中的一个主要挑战，外排机制被认为会降低抗生素的疗效。在本研究中，我们调查了天然黄酮类化合物柚皮素作为金黄色葡萄球菌1199和1199B菌株的抗菌剂和外排泵抑制剂的潜力。研究采用了最低抑菌浓度（MIC）测定、溴化乙锭（EtBr）荧光发射增强测定、细胞膜通透性测定以及计算机模拟分子对接和ADME预测测定。柚皮素未显示出相关抗菌活性（MIC≥1024μg/mL）。然而，它增强了诺氟沙星和EtBr的作用，降低了它们的MIC，并增加了EtBr的荧光发射，表明可能抑制了NorA外排泵。细菌膜通透性未受到显著影响。分子对接测定表明，柚皮素与氯丙嗪结合位点相互作用，并且比氯丙嗪-NorA复合物具有更有利的亲和能。ADME预测显示其具有良好的物理化学性质、良好的口服吸收、代谢稳定性和中枢神经系统安全性。因此，柚皮素通过与NorA蛋白有效相互作用抑制外排，显示出逆转诺氟沙星在金黄色葡萄球菌中疗效的潜力，表明其具有抗细菌耐药性的治疗潜力。
