Fluoride triggers lysis in Streptococcus mutans by inhibition of Clp protease complex leading to an unabated competence cascade

Fluoride has long been known to possess antimicrobial properties, triggering extensive lysis in diverse bacterial species. Surprisingly, given the ubiquity of fluoride in oral healthcare, the underlying mechanisms by which fluoride kills bacteria remain unknown. Using dental pathogen Streptococcus mutans as a model, we show that fluoride elicits an uncontrolled stress response characterized by upregulation of competence pathways and extensive cell wall degradation. While limited autolysis is adaptive, we show that fluoride subverts the typical tight temporal control of the competence-associated alternative sigma factor ComX by specifically inhibiting assembly and activity of Clp ATPases, thus disrupting proteolytic degradation of ComX. Phenylalanine partially restores Clp protease activity, explaining the frequent presence of a gene encoding chorismate mutase in fluoride-responsive operons. Together, these findings reveal the molecular mechanism that underlie fluoride-dependent lysis in bacteria, and identify new pathways that could be exploited to potentiate the antimicrobial effects of oral fluoride.