Aix Marseille Université, INSERM, SSA, MCT, Marseille, France.
Aix Marseille Université, CNRS, CINaM UMR 7325, Campus de Luminy, Marseille, France.
Arch Pharm (Weinheim). 2023 Jul;356(7):e2300103. doi: 10.1002/ardp.202300103. Epub 2023 May 18.
Antibiotic resistance has increased the demand for novel treatments against multidrug-resistant microorganisms. In the research literature, 5-fluorouracil (5-FU) was proposed as an alternative due to its intrinsic antibacterial property. However, given its toxicity profile at high doses, its use in antibacterial therapy is dubious. In the quest for improving the efficacy of 5-FU, the present study intends to synthesise 5-FU derivatives and assess their susceptibility and mechanism against pathogenic bacteria. It was found that the compounds having tri-hexylphosphonium substitution on both nitrogen groups of 5-FU (6a, 6b and 6c) had considerable activity against both Gram-positive and Gram-negative bacteria. Among the active compounds, those with an asymmetric linker group 6c were found to have higher antibacterial efficacy. However, no conclusive efflux inhibition activity was found. As elucidated by electron microscopy studies, these self-assembling active phosphonium-based 5-FU derivatives caused considerable septal damage and cytosolic alterations in Staphylococcus aureus cells. In Escherichia coli, these compounds triggered plasmolysis. Interestingly, the minimal inhibitory concentration (MIC) of the most potent 5-FU derivative 6c remained constant, regardless of the bacteria's resistance profile. Further analysis revealed that compound 6c generated significant alterations in membrane permeabilization and depolarization in S. aureus and E. coli cells at the MIC. Compound 6c was found to substantially impede bacterial motility, suggesting its importance in regulating bacterial pathogenicity. Additionally, the nonhaemolytic activity of 6c suggested that it could be a potential therapeutic option for treating multidrug-resistant bacterial infections.
抗生素耐药性增加了对多药耐药微生物的新型治疗方法的需求。在研究文献中，5-氟尿嘧啶（5-FU）因其固有抗菌特性而被提议作为替代物。然而，鉴于其高剂量的毒性特征，其在抗菌治疗中的应用是值得怀疑的。在寻求提高 5-FU 的疗效的过程中，本研究旨在合成 5-FU 衍生物，并评估它们对致病菌的敏感性和作用机制。结果发现，在 5-FU 的两个氮原子上都具有三己基膦取代的化合物（6a、6b 和 6c）对革兰氏阳性菌和革兰氏阴性菌都具有相当的活性。在活性化合物中，具有不对称连接基团的化合物 6c 具有更高的抗菌功效。然而，没有发现明确的外排抑制活性。正如电子显微镜研究所阐明的，这些自组装的活性磷基 5-FU 衍生物导致金黄色葡萄球菌细胞中相当大的隔膜损伤和细胞质改变。在大肠杆菌中，这些化合物引发质壁分离。有趣的是，最有效 5-FU 衍生物 6c 的最小抑菌浓度（MIC）保持不变，无论细菌的耐药谱如何。进一步的分析表明，化合物 6c 在 MIC 下对金黄色葡萄球菌和大肠杆菌细胞的膜通透性和去极化产生了显著的改变。化合物 6c 被发现极大地抑制了细菌的运动性，表明其在调节细菌致病性方面的重要性。此外，6c 的非溶血活性表明它可能是治疗多药耐药细菌感染的潜在治疗选择。
