ADMET analysis and evaluation of the effect of ortho-eugenol on the QacA/B efflux pump of Staphylococcus aureus

Jessyca Nayara Mascarenhas Lima , Cristina Rodrigues dos Santos Barbosa , Joycy Francely Sampaio dos Santos , Jackelyne Roberta Scherf , Thiago Sampaio de Freitas , Larissa da Silva , Nair Silva Macêdo , Catarina Martins Tahim , Elaine Cristina Pereira Lucetti , Emmanuel Silva Marinho , Hélcio Silva dos Santos , Micheline Azevedo Lima , Henrique Douglas Melo Coutinho , Francisco Assis Bezerra da Cunha
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Abstract

Antimicrobial resistance (AMR) is a significant global problem, with Staphylococcus aureus being a prominent multidrug-resistant bacterium, mainly due to mechanisms such as β-lactamase production and the QacA/B efflux pump system. These mechanisms impede effective treatment of the infection, necessitating the development of innovative therapeutic strategies. In this context, natural products such as ortho-eugenol, a synthetic isomer of eugenol, have attracted attention for their potential to modulate bacterial resistance. This study evaluated the antimicrobial activity of ortho-eugenol against S. aureus K4414, a strain harboring the QacA/B efflux pump. Despite having a minimum inhibitory concentration (MIC) of ≥ 1024 μg/mL, indicating weak antibacterial activity, its combination with penicillin resulted in a fivefold reduction in the MIC of the antibiotic (from 512 μg/mL to 101.6 μg/mL). This potentiating effect was not observed with the standard efflux pump inhibitor chlorpromazine, suggesting that the mechanism is not related to QacA/B inhibition but likely involves β-lactamase inhibition, as confirmed by the combination of ampicillin with sulbactam. In addition, ortho-eugenol in combination with ethidium bromide (EtBr) increased the MIC of EtBr, suggesting an antagonistic interaction. In contrast, chlorpromazine with EtBr decreased its MIC, confirming the functionality of the QacA/B efflux pump. Biophysical and predictive analyses revealed that ortho-eugenol has lipophilic properties and moderate metabolic stability, making it suitable for oral bioavailability with low central nervous system toxicity. However, a structural vulnerability related to the isolated alkene group was identified, indicating potential epoxidation during phase I metabolism, warranting controlled dosing. These findings highlight the potential of ortho-eugenol as a β-lactamase inhibitor.
邻丁香酚对金黄色葡萄球菌QacA/B外排泵影响的ADMET分析与评价
抗微生物药物耐药性(AMR)是一个重要的全球性问题,金黄色葡萄球菌是一种突出的多重耐药细菌,主要是由于β-内酰胺酶产生和QacA/B外排泵系统等机制。这些机制阻碍了感染的有效治疗,因此需要开发创新的治疗策略。在这种情况下,天然产物,如邻丁香酚,丁香酚的合成异构体,因其调节细菌耐药性的潜力而引起了人们的注意。本研究评价了邻丁香酚对含有QacA/B外排泵的金黄色葡萄球菌K4414的抑菌活性。尽管其最低抑菌浓度(MIC)≥ 1024 μg/mL,表明抗菌活性较弱,但与青霉素联用可使抗生素的MIC降低5倍(从512 μg/mL降至101.6 μg/mL)。标准外排泵抑制剂氯丙嗪未观察到这种增强作用,提示其机制与QacA/B抑制无关,而可能涉及β-内酰胺酶抑制,氨苄西林与舒巴坦合用证实了这一点。此外,邻丁香酚与溴化乙啶(EtBr)联合使用可增加EtBr的MIC,表明存在拮抗相互作用。相比之下,氯丙嗪与EtBr降低了其MIC,证实了QacA/B外排泵的功能。生物物理和预测分析表明,邻丁香酚具有亲脂性和中等代谢稳定性,适合用于口服生物利用度,中枢神经系统毒性低。然而,鉴定出与分离的烯烃基团相关的结构脆弱性,表明在I期代谢过程中可能发生环氧化,因此需要控制剂量。这些发现突出了邻丁香酚作为β-内酰胺酶抑制剂的潜力。
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