For decades, fluoride has been used extensively as an anti-caries agent. It not only protects dental hard tissue, but also inhibits bacterial growth and metabolism. The antimicrobial action of fluoride is shown in three main aspects: the acidogenicity, acidurance, and adherence to the tooth surface. To counteract the toxic effect of fluoride, oral bacteria are able to develop resistance to fluoride through either phenotypic adaptation or genotypic changes. Strains that acquire fluoride resistance through the latter route show stable resistance and can usually resist much higher fluoride levels than the corresponding wild-type strain. This review summarizes the characteristics of fluoride-resistant strains and explores the mechanisms of fluoride resistance, in particular the recent discovery of the fluoride exporters. Since the fluoride resistance of the cariogenic bacterium Streptococcus mutans has been studied most extensively, this review mainly discusses the findings related to this species.

It is known that fluoride-resistant microorganisms are different from fluoride-sensitive ones in growth, adherence and metabolic activity. It was hypothesized that these phenotypic differences were due to stable genotypic changes in the fluoride-resistant strains. However, until now, no studies have reported these genotypic changes. The aim of this study is to identify such changes in a fluoride-resistant Streptococcus mutans strain (C180-2FR) using whole-genome shotgun (WGS) sequencing and to examine the potential function of the identified mutations by comparing gene expression between the fluoride-sensitive (C180-2) and C180-2FR strains. We performed 50 bp paired-end Illumina shotgun sequencing for both strains. Through extensive bioinformatic analysis, we were able to identify 8 single nucleotide polymorphisms (SNPs) in the genome of C180-2FR, which were further confirmed by Sanger sequencing. Expression of the genes containing or in proximity to the SNPs in C180-2 and C180-2FR was then quantified by real-time PCR. A gene cluster containing genes coding for fluoride antiporters was up-regulated 10-fold in C180-2FR when compared to that in C180-2, independent of growth phase. Two SNPs are located in this gene cluster, one in its promoter region and the other in its protein-coding region. In addition, one gene, which codes for a putative glycerol uptake facilitator protein, was found to be down-regulated by 60% in C180-2FR at an early growth phase. The promoter region of this gene contained a SNP. No difference in expression was found for the other SNP-containing genes. In summary, using WGS sequencing, we were able to uncover genetic changes in the genome of a fluoride-resistant strain. These findings can provide new insights into the mechanism of microbial fluoride resistance.