Department of Biological Chemistry, Regional University of Cariri (URCA), Crato, CE 63105-010, Brazil.
Oswaldo Cruz Foundation (Fiocruz), Fiocruz Ceará, Eusébio, CE 60180-900, Brazil.
Biomed Pharmacother. 2024 Nov;180:117600. doi: 10.1016/j.biopha.2024.117600. Epub 2024 Oct 30.
This study aimed to evaluate the effects of liposome-encapsulated eugenol-based thiazolic derivatives against efflux pump-carrying bacteria. The Minimum Inhibitory Concentration (MIC) was determined to evaluate the antibacterial activity and antibiotic potentiation against Pseudomonas aeruginosa and Staphylococcus aureus, as well as to analyze the inhibition of efflux pumps in S. aureus strains 1199B and K2068 in the ethidium bromide assay. The direct antibacterial activity analysis showed no clinically relevant results since the compounds presented MICs ≥1024 µg/mL. Regarding the analysis of antibiotic potentiation against multidrug-resistant (MDR) strains of S. aureus, compound LF16 reduced norfloxacin MIC from 128 µg/mL to 64 µg/mL. All associated with gentamicin caused a significant antibiotic MIC reduction. None of the compounds could potentate the activity of norfloxacin against P. aeruginosa. However, all of them potentiated the activity of gentamicin against the same strain. Only the LF 26 caused a significant MIC reduction in the ethidium bromide assay, suggesting efflux inhibition in the S. aureus 1199B strain. Similar results were observed with the K2068 strain. Observing antibiotic MIC reduction S. aureus strains carrying the NorA and MepA proteins brought additional evidence of efflux pump inhibition. Our results indicate that while eugenol-based thiazoles didn't exhibit direct activity, they can potentiate the antibiotics activity against MDR strains of P. aeruginosa and S. aureus. Among them, compound LF 26 potentiated the inhibitory effects of ethidium bromide and antibiotics against S. aureus strains carrying the NorA and MepA proteins, indicating a potential role of this class of compounds as efflux pump inhibitors.
本研究旨在评估脂质体包封的基于丁香酚的噻唑衍生物对携带外排泵的细菌的作用。测定最低抑菌浓度（MIC）以评估对铜绿假单胞菌和金黄色葡萄球菌的抗菌活性和抗生素增效作用，并分析溴化乙锭试验中金黄色葡萄球菌 1199B 和 K2068 菌株的外排泵抑制作用。直接抗菌活性分析没有显示出临床相关的结果，因为这些化合物的 MIC 值均≥1024µg/mL。关于化合物 LF16 将诺氟沙星 MIC 从 128µg/mL 降低至 64µg/mL 的多药耐药（MDR）金黄色葡萄球菌的抗生素增效分析，所有与庆大霉素相关的药物均导致抗生素 MIC 显著降低。没有一种化合物能够增强诺氟沙星对铜绿假单胞菌的活性。然而，所有化合物都增强了庆大霉素对同一菌株的活性。只有 LF26 在溴化乙锭试验中引起 MIC 显著降低，提示在金黄色葡萄球菌 1199B 菌株中外排泵抑制。K2068 菌株也观察到了类似的结果。观察到携带 NorA 和 MepA 蛋白的金黄色葡萄球菌菌株的抗生素 MIC 降低，这为外排泵抑制提供了额外的证据。我们的结果表明，虽然基于丁香酚的噻唑类化合物没有表现出直接活性，但它们可以增强抗生素对铜绿假单胞菌和金黄色葡萄球菌 MDR 菌株的活性。其中，化合物 LF26 增强了溴化乙锭和抗生素对携带 NorA 和 MepA 蛋白的金黄色葡萄球菌菌株的抑制作用，表明该类化合物可能具有外排泵抑制剂的作用。
