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.
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The authors express their sincere gratitude to Prof. Ronald R. Breaker, Dr. Gayan Sanjeewa, Dr. Narasimhan Sudarsan and Dr. Keith Corbino, from the Department of Molecular Biophysics and Biochemistry, Yale University for their generous support in the completion of this research study. Authors are also thankful to Dr. Dinesh C. Aluthge, Department of Chemistry, University of Colombo for his valuable suggestions, which helped them to improve the quality of the paper.
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Dias, S.A.D.N., Divyasorubini, S., Gamage, K.T.J. et al. Na+/K+ carrier ionophore antibiotics valinomycin and monensin enhance the antibacterial activity of fluoride. J Antibiot 76, 425–429 (2023). https://doi.org/10.1038/s41429-023-00619-w