Due to the continued increase of bacterial resistance to both commonly used antibiotics, as well as antibiotics of last resort, new antibacterial strategies are needed. We recently discovered a riboswitch class whose representatives selectively bind fluoride and control the expression of numerous genes involved in mitigating the toxic effects of fluoride, an inhibitor of numerous metabolic enzymes. Most commonly, fluoride riboswitches activate the expression of genes coding for fluoride transporters, which act to lower intracellular levels of fluoride. We hypothesized that small molecules that either block these channels or otherwise enhance fluoride toxicity by some other mechanism could serve, in conjunction with fluoride, as a new type of topical antibiotic formulation. To identify such compounds, we performed a high-throughput screen of small, drug-like compounds, using a fluoride-responsive reporter to assess their ability to increase intracellular fluoride concentrations. Several different series of compounds were identified that sensitize Escherichia coli to fluoride. Preliminary SAR analysis is indicative of the existence of specific pharmacophore structures. We also demonstrate that a series of known antibacterial or antifungal compounds that compromise membrane integrity, and thereby allow fluoride to enter cells, are more effective antibiotics when supplied in combination with fluoride.

Progress towards antibacterial and antifungal fluoride toxicity agonists

246th National Meeting (2013)

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