The application of certain antibiotics has been clinically limited due to antibiotic resistance and host toxicity. For example, membrane destabilizing ionophores such as valinomycin exert their antibiotic activity by conducting ions through the cell membrane but can cause host toxicity by perturbing intracellular ion homeostasis. Nonetheless, valinomycin has a remarkable antiviral activity against human coronaviruses, including SARS-CoV-2. Therefore, translating such compounds to clinical settings requires them to remain non-toxic to the host. Fluoride is a toxic anion that has both antimicrobial and viricidal properties. However, the cellular uptake of fluoride is limited due to the bacterial cell envelope. Accordingly, compounds that enhance the permeability of cell membranes should induce strong fluoride toxicity in pathogens by enhancing fluoride uptake. Therefore, combination regimens such as ionophore antibiotics and fluoride may increase treatment efficacy, while lowering the doses of host-toxic antibiotics. In this study, we demonstrate that fluoride significantly enhances the antibacterial activity of the carrier ionophore antibiotics; valinomycin and monensin. Cell growth assays were performed by incubating Bacillus subtilis at 37 °C with monensin (0.2 µg/ml) or valinomycin (50 µg/ml) with varying concentrations of NaF. Next, absorbance readings at 600 nm were obtained after 16 hours of incubation. Our results demonstrate that the potency of monensin and valinomycin was increased by 5 fold and 2 fold respectively, in the presence of sub-inhibitory concentrations of NaF (~100 mM). Similar results were observed for other Gram-positive bacteria such as Bacillus megaterium. In contrast, neither of the antibiotics exert any synergism with fluoride against the Gram-negative bacterium E. coli. Overall, it can be suggested that the two ionophore antibiotics may increase the cellular uptake of fluoride to exert synergistic bacterial growth inhibition by enhancing intracellular fluoride toxicity. This study provides new insights to design effective therapeutic combination regimens for deleterious diseases that have plagued humans

Fluoride enhances the antibacterial activity of Na+/K+ carrier ionophore antibiotics

ACS Spring Meeting 2021

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