Sodium Ascorbate Kills Candida Albicans in Vitro Via Iron-Catalyzed Fenton Reaction: Importance of Oxygenation and Metabolism

Abstract

aim: Ascorbate can inhibit growth and even decrease viability of various microbial species including Candida albicans. However the optimum conditions and the mechanism of action are unclear. Materials/methodology: Candida albicans shaken for 90 min in a buffered solution of ascorbate (90 mM) gave a 5-log reduction of cell viability, while there was no killing without shaking, in growth media with different carbon sources or at 4°C. Killing was inhibited by the iron chelator 2,2′-bipyridyl. Hydroxyphenyl fluorescein probe showed the intracellular generation of hydroxyl radicals. Results/conclusion: Ascorbate-mediated killing of C. albicans depends on oxygenation and metabolism, involves iron-catalyzed generation of hydroxyl radicals via Fenton reaction and depletion of intracellular NADH. Ascorbate could serve as a component of a topical antifungal therapy. Keywords• ascorbate • Candida albicans • hydroxyl radicals • oxidative stress • vitamin C Candida albicans is a major opportunistic fungal pathogen that is associated with a range of clinical conditions. The organism can lead to superficial infections of genital, oral and cutaneous sites as well as systemic infections, especially in hospitalized and/or immunocompromised patients, such as those suffering from AIDS or undergoing chemotherapy [1][2][3][4]. Although most superficial infections caused by C. albicans are not life threatening, these infections can have debilitating effects on the patient's quality of life. Several classes of antifungal agents (e.g., azoles, echinocandins) have been developed which are active against Candida infections; however, possible drug interactions and adverse side-effects, emergence of drug-resistant isolates, as well as the high costs of some of these agents underscore the necessity for development of additional treatment alternatives [3,5].Ascorbate (vitamin C, ascorbic acid) is an essential vitamin and is considered to be a potent antioxidant owing to its ability to act as an electron-donating reducing agent, and a quencher of reactive oxygen species (ROS) [6]. However, there is also increasing evidence that at pharmacologic concentrations, ascorbate can exert pro-oxidant effects via the reduction of transition metal ions, such as iron and copper [7]. Previous studies have shown that high-dose ascorbate exerts selective cytotoxic effects on cancer cells both in vitro and in vivo [6,8]. There have also been several clinical trials in cancer patients, testing the effects of high-dose ascorbate either alone or in For reprint orders, please contact: reprints@futuremedicine.com

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“…3). Importantly, ThThDP has been attributed to have antimetabolic activity (ThDP antagonist) (25) and reactive oxygen species, such as peracetate, inhibit C. albicans growth via NADH depletion (26). These factors, in addition to ThDP's being replenished at a metabolic cost to cells, could be major contributors to biocidal activity.…”

Intravenous vitamin C for reduction of cytokines storm in acute respiratory distress syndrome

“…The generation of reactive oxygen species through the reduction of transition metal is possible [89]. It was found that a very high-dose of one sodium salt of ascorbic acid (90 mM) kills Candida albicans in-vitro through an ironcatalyzed Fenton reaction [90]. An iron chelator 2,2′-bipyridyl inhibited this effect.…”

A Membrane-Targeted Peptide Inhibiting PtxA of Phosphotransferase System Blocks <b><i>Streptococcus mutans</i></b>

“…As has been observed in previous studies, ascorbic acid combined with an antibiotic, or used individually, has been shown to be effective in the treatment of infectious diseases [Mal et al, 2012;Avci et al, 2016]. Hence, C10-KKWW might target PtxA to inhibit S. mutans, especially when L-ascorbate levels are at the optimal concentration and present at the optimal time.…”

“…On the other hand, it also exerts pro-oxidant activity at high concentrations [Avci et al, 2016]. Based on these characteristics, it has been defined as being either an antimicrobial or an anticancer agent.…”

“…Sodium L-ascorbate is usually used as an alternative to L-ascorbate itself based on the same physiological application and neutral pH. To some degree, L-ascorbate or sodium L-ascorbate can be used either individually or in combination as antimicrobial agents, [Mal et al, 2012;Avci et al, 2016] therefore, TVL or exogenous sodium L-ascorbate can be considered an L-ascorbate source.…”