Enhancement of Antimycotic Activity of Amphotericin B by Targeting the Oxidative Stress Response of Candida and Cryptococcus with Natural Dihydroxybenzaldehydes

Abstract

In addition to the fungal cellular membrane, the cellular antioxidant system can also be a viable target in the antifungal action of amphotericin B (AMB). Co-application of certain redox-potent natural compounds with AMB actually increases efficacy of the drug through chemosensitization. Some redox-potent chemosensitizers and AMB perturb common cellular targets, resulting in synergistic inhibition of fungal growth. Chemosensitizing activities of four redox-potent benzaldehydes were tested against clinical and reference strains of Candida albicans, C. krusei, C. tropicalis, and Cryptococcus neoformans in combination with AMB, based on assays outlined by the European Committee on Antimicrobial Susceptibility Testing. Two dihydroxybenzaldehydes (DHBAs), i.e., 2,3-DHBA and 2,5-DHBA, significantly enhanced activity of AMB against most strains, as measured by lower minimum inhibitory concentrations and/or minimum fungicidal concentrations (MFCs). A non-hydroxylated benzaldehyde, trans-cinnamaldehyde, showed chemosensitizing activity through lower MFCs, only. Contrastingly, a methoxylated benzaldehyde (3,5-dimethoxybenzaldehyde) had no chemosensitizing activity, as all strains were hypertolerant to this compound. Bioassays using deletion mutants of the model yeast, Saccharomyces cerevisiae, indicated DHBAs exerted their chemosensitizing activity by targeting mitochondrial superoxide dismutase. This targeting, in turn, disrupted the ability of the yeast strains to respond to AMB-induced oxidative stress. These in vitro results indicate that certain DHBAs are potent chemosensitizing agents to AMB through co-disruption of the oxidative stress response capacity of yeasts. Such redox-potent compounds show promise for enhancing AMB-based antifungal therapy for candidiasis and cryptococcosis.

Heterocycle Thiazole Compounds Exhibit Antifungal Activity through Increase in the Production of Reactive Oxygen Species in the Cryptococcus neoformans-Cryptococcus gattii Species Complex

“…This would explain the result found by our group, where there is an antagonistic interaction between these thiazoles and amphotericin B against various isolates of C. neoformans and C. gattii (Table 4) (26). Some studies have demonstrated that amphotericin B, in addition to the action on the membrane ergosterol, also acts by promoting an increase in intracellular H 2 O 2 and lipid peroxidation, which helps the fungicide action of this drug and prevents the emergence of resistant organisms (33,34).…”

Delicate Metabolic Control and Coordinated Stress Response Critically Determine Antifungal Tolerance of Candida albicans Biofilm Persisters

“…The control of oxidative stress may be a common mechanism for bacterial tolerance (58). It has been reported that targeting of the oxidative stress response of Candida is able to enhance the efficacy of AMB treatment (59). Exposure of C. albicans planktonic cultures to AMB at a concentration equivalent to the MIC might result in the upregulation of multiple proteins involved in oxidative stress adaptation (60).…”

Visualization analysis of the vacuole-targeting fungicidal activity of amphotericin B against the parent strain and an ergosterol-less mutant of Saccharomyces cerevisiae

“…AmB lethality can also occur via the inhibition of protein synthesis through loss of intracellular K + and ATP depletion (Alonso et al, 1979). In addition, AmB is known to cause oxidative damage in cells of the pathogenic fungus Candida albicans by generating superoxide anions (Kim et al, 2012). We previously demonstrated that lethal concentrations of AmB caused dramatic disruption of the spherical architecture of vacuoles in Saccharomyces cerevisiae and C. albicans cells, and since then, this AmB-induced intracellular event has been considered the direct cause of its lethality (Borjihan et al, 2009;Ogita et al, 2006;Ogita et al, 2012).…”