Fluoride and organic weak acids as modulators of microbial physiology

HF crosses biological membranes through water channels, including aquaporins.

“HF is such a small molecule that it would cross biological membranes through water channels, including aquaporins (Marquis et al., 2003).”

Many actions of F− are connected to its weak-acid (or strong-base) character, making its mechanism of action comparable to that of organic weak acids, which de-energize the cell membrane by dissipating ΔpH.

“Since many of the actions of F− are connected to its weak‐acid (or strong‐base) character, the mechanism of action of this anion is comparable to that of organic weak acids, e.g. metabolic acids (acetate), food preservatives, non‐steroidal anti‐inflammatory agents and fatty acids—all of which act to de‐energize the cell membrane by dissipating ΔpH (Marquis et al., 2003).”

CrcB export proteins function as passive fluoride-specific ion channels that require Na+ ions for transport activity.

“In contrast, CrcB export proteins function as passive fluoride-specific ion channels that require Na+ ions for transport activity (4, 5, 23–26).”

Many of the actions of fluoride are related to those of organic weak acids, including metabolic acids, fatty acids, and benzoic acid, which de-energize the cell membrane.

“Importantly, many of the actions of fluoride are related to those of organic weak acids, including metabolic acids, fatty acids, and benzoic acid—all of which de-energize the cell membrane (26).”

If fluoride is formed in the cytoplasm, it would be directly toxic, inhibiting critical enzymes at concentrations as low as 70 μM.

“If formed in the cytoplasm, fluoride would be directly toxic, inhibiting critical enzymes at concentrations as low as 70 μM (23, 24).”

Over-the-counter fluoride products like toothpaste and rinses contain fluoride in the range of 12 to 60 mM fluoride, high enough to have antimicrobial effects.

“Over-the-counter fluoride products like toothpaste and rinses contain fluoride in the range of 12 to 60 mM fluoride (226 to 1100 ppm F-), which is high enough to have such antimicrobial effects (11).”

Fluoride ion (F−) is a common xenobiotic in natural environments that causes broad-spectrum harm to metabolic pathways.

“One particularly ancient, pernicious threat is posed by fluoride ion (F−), a common xenobiotic in natural environments that causes broad-spectrum harm to metabolic pathways.”

Mitigation of fluoride stress is multi-faceted, with some bacteria sensing toxic fluoride with a riboswitch, producing enzymes less sensitive to fluoride, inducing fluoride-specific membrane export proteins, and carrying out other as-yet-to-be defined functions.

“Mitigation of fluoride stress has been shown to be multi-faceted, with some bacteria sensing toxic fluoride with a riboswitch, producing enzymes less sensitive to fluoride, inducing fluoride-specific membrane export proteins, and carrying out other as-yet-to-be defined functions (5, 8, 9).”

Membrane permeation of the weak acid HF is the major route to fluoride accumulation in the cytosol, and fluoride exposure is correlated with cytoplasmic acidification.

“Since membrane permeation of the weak acid HF is the major route to fluoride accumulation in the cytosol92, fluoride exposure is correlated with cytoplasmic acidification21.”

The charged species (H+ and F−) cannot diffuse back across the membrane out of the cell, and thus accumulate, a process known as weak acid accumulation.

“These charged species cannot diffuse back across the membrane out of the cell, and thus accumulate, a process known as weak acid accumulation, or ion-trapping(13).”