Bicarbonate Alters Bacterial Susceptibility to Antibiotics by Targeting the Proton Motive Force

Abstract

The antibacterial properties of sodium bicarbonate have been known for years, yet the molecular understanding of its mechanism of action is still lacking. Utilizing chemical-chemical combinations, we first explored the effect of bicarbonate on the activity of conventional antibiotics to infer on the mechanism. Remarkably, the activity of 8 classes of antibiotics differed in the presence of this ubiquitous buffer. These interactions and a study of mechanism of action revealed that, at physiological concentrations, bicarbonate is a selective dissipater of the pH gradient of the proton motive force across the cytoplasmic membrane of both Gram-negative and Gram-positive bacteria. Further, while components that make up innate immunity have been extensively studied, a link to bicarbonate, the dominant buffer in the extracellular fluid, has never been made. Here, we also explored the effects of bicarbonate on components of innate immunity. Although the immune response and the buffering system have distinct functions in the body, we posit there is interplay between these, as the antimicrobial properties of several components of innate immunity were enhanced by a physiological concentration of bicarbonate. Our findings implicate bicarbonate as an overlooked potentiator of host immunity in the defense against pathogens. Overall, the unique mechanism of action of bicarbonate has far-reaching and predictable effects on the activity of innate immune components and antibiotics. We conclude that bicarbonate has remarkable power as an antibiotic adjuvant and suggest that there is great potential to exploit this activity in the discovery and development of new antibacterial drugs by leveraging testing paradigms that better reflect the physiological concentration of bicarbonate.

Uncovering the hidden antibiotic potential of Cannabis

“…2). To probe the possibility that CBG selectively dissipated membrane potential (Δψ) component of proton motive force, we tested for synergy with sodium bicarbonate, a known perturbant of ΔpH, that has been shown to synergize with molecules that reduce Δψ 25 . A lack of synergy between these compounds suggested CBG disrupts the integrity of the cytoplasmic membrane (Supplementary Fig.…”

Thinking Outside the Box—Novel Antibacterials To Tackle the Resistance Crisis

“…All of these components modulate various pathways and are mainly causative for the altered in vivo efficiency of antibiotics. [77,78] Despite these advancements of in vitro AST,t he full complexity of bacterial infections in vivo can hardly be simulated. [75,76] Ar ecent study by Ersoy et al revealed that the antibiotic susceptibility of various clinical isolates strongly depends on the medium used for in vitro cultivation.…”

“…[77] Similarly, the addition of physiological concentrations of NaHCO 3 to standard MHB medium resulted in ah ost-mimicking environment, which suggests that the salt is akey component that contributes to antibiotic susceptibility in vivo. [77,78] Despite these advancements of in vitro AST,t he full complexity of bacterial infections in vivo can hardly be simulated. Therefore,h igh-throughput infection screening has become av aluable tool, especially for secondary antibiotic screens.…”

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“…All diese Komponenten regulieren zahlreiche bakterielle Stoffwechselwege und sind der Hauptgrund füreine veränderte Invivo-Effizienz von Antibiotika. [77,78] Tr otz der beschriebenen Fortschritte des In-vitro-AST kann die volle Komplexitätd er bakteriellen Infektion in vivo jedoch kaum simuliert werden. Ein leicht umsetzbarer und sehr effektiver Ansatz ist die Substitution von geläufigen Vollmedien durch Minimalmedien.…”

“…[75,76] [77] In ähnlicher Weise führte die Zugabe von physiologischen Konzentrationen von NaHCO 3 zum geläufigen MHB-Medium zu einer Wirt-ähnlichen Umgebung.D as Salz scheint somit eine entscheidende Komponente fürdie Antibiotika-Empfindlichkeit in vivo zu sein. [77,78] Tr otz der beschriebenen Fortschritte des In-vitro-AST kann die volle Komplexitätd er bakteriellen Infektion in vivo jedoch kaum simuliert werden. Hochdurchsatz-Infektions-Screenings haben sich daher heute zu einer wertvollen Methode,i nsbesondere fürs ekundäre Antibiotika-Screenings, entwickelt.…”