Multi-drug-resistant Staphylococcus aureus infections necessitate novel antibiotic development. D-3263, a transient receptor potential melastatin member 8 (TRPM8) agonist, has potential antineoplastic properties. Here, we reported the antibacterial and antibiofilm activities of D-3263. Minimum inhibitory concentrations (MICs) against S. aureus, Enterococcus faecalis and E. faecium were ≤ 50 µM. D-3263 exhibited bactericidal effects against clinical methicillin-resistant S. aureus (MRSA) and E. faecalis strains at 4× MIC. Subinhibitory D-3263 concentrations effectively inhibited S. aureus and E. faecalis biofilms, with higher concentrations also clearing mature biofilms. Proteomic analysis revealed differential expression of 29 proteins under 1/2 × MIC D-3263, influencing amino acid biosynthesis and carbohydrate metabolism. Additionally, D-3263 enhanced membrane permeability of S. aureus and E. faecalis. Bacterial membrane phospholipids phosphatidylethanolamine (PE), phosphatidylglycerol (PG), and cardiolipin (CL) dose-dependently increased D-3263 MICs. Overall, our data suggested that D-3263 exhibited potent antibacterial and antibiofilm activities against S. aureus by targeting the cell membrane.

中文翻译：

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D-3263对金黄色葡萄球菌的抗菌活性及机制


多重耐药金黄色葡萄球菌感染需要新型抗生素的开发。 D-3263 是一种瞬时受体潜在褪黑素成员 8 (TRPM8) 激动剂，具有潜在的抗肿瘤特性。在这里，我们报道了 D-3263 的抗菌和抗生物膜活性。对金黄色葡萄球菌、粪肠球菌和屎肠球菌的最低抑菌浓度 (MIC) ≤ 50 µM。 D-3263 在 4× MIC 下对临床耐甲氧西林金黄色葡萄球菌 (MRSA) 和粪肠球菌菌株表现出杀菌作用。亚抑制浓度的 D-3263 可有效抑制金黄色葡萄球菌和粪肠球菌生物膜，较高浓度还可清除成熟的生物膜。蛋白质组学分析揭示了 1/2 × MIC D-3263 下 29 种蛋白质的差异表达，影响氨基酸生物合成和碳水化合物代谢。此外，D-3263 增强了金黄色葡萄球菌和粪肠球菌的膜通透性。细菌膜磷脂磷脂酰乙醇胺 (PE)、磷脂酰甘油 (PG) 和心磷脂 (CL) 剂量依赖性地增加 D-3263 MIC。总体而言，我们的数据表明，D-3263 通过靶向细胞膜，对金黄色葡萄球菌表现出有效的抗菌和抗生物膜活性。