Abstract：
Fluoride is routinely used as a highly effective antibacterial agent that interferes with bacterial metabolism through fundamentally different mechanisms. One of the major bacterial evasion mechanisms against fluoride is the impermeability of cell envelope to the anion that limits its cellular uptake. Therefore, translating such compounds to clinical settings requires novel mechanisms to facilitate the uptake of membrane-impermeant molecules. Published data have indicated antibiotic synergy between fluoride and membrane destabilizing agents that induce strong fluoride toxicity in bacteria via enhancing the permeability of bacterial membranes to fluoride. Here, we report a similar mechanism of antibiotic synergy between fluoride and potassium ion carriers, valinomycin and monensin against Gram-positive bacteria, B. subtilis and S. aureus. Molecular dynamics simulations were performed to understand the effect of potassium on the binding affinity of fluoride to monensin and valinomycin. The trajectory results strongly indicated that the monensin molecules transport fluoride ions across the cell membrane via formation of ion-pair between the monensin-K+ complex and a fluoride. This study provides new insights to design novel compounds to enhance the uptake of small toxic anions via synergistic interactions and thus exert strong antibacterial activity against a wide variety of pathogens.
摘要：
氟化物通常用作高效抗菌剂,其通过根本不同的机制干扰细菌代谢。针对氟化物的主要细菌逃避机制之一是细胞包膜对限制其细胞摄取的阴离子的不渗透性。因此,将此类化合物转化为临床环境需要新的机制来促进膜不渗透分子的摄取。公开的数据表明氟化物和膜去稳定剂之间的抗生素协同作用,其通过增强细菌膜对氟化物的渗透性而在细菌中诱导强氟化物毒性。这里,我们报道了氟和钾离子载体之间的抗生素协同作用的类似机制，缬霉素和莫能菌素抗革兰氏阳性菌，枯草芽孢杆菌和金黄色葡萄球菌。进行了分子动力学模拟以了解钾对氟化物与莫能菌素和缬氨酸霉素的结合亲和力的影响。轨迹结果强烈表明，莫能菌素分子通过在莫能菌素-K复合物和氟化物之间形成离子对，将氟离子转运穿过细胞膜。这项研究为设计新型化合物提供了新的见解，以通过协同相互作用增强对小毒性阴离子的吸收，从而对各种病原体发挥强大的抗菌活性。
