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.
Highlights
There has been a persistent effort to improve efficacy of conventional antimycotic drugs, especially for treatment of human candidiasis and cryptococcosis
The lipid-based AMBs are generally recommended for patients who Abbreviations: AMB, amphotericin B; CFU, colony forming unit; Cinn, cinnamaldehyde; DHBA, dihydroxybenzaldehyde; 2,3-DHBA, 2,3dihydroxybenzaldehyde; 2,5-DHBA, 2,5-dihydroxybenzaldehyde; 3,5-DMBA, 3,5-dimethoxybenzaldehyde; DMSO, dimethyl sulfoxide; EUCAST, European Committee on Antimicrobial Susceptibility Testing; FFCI, fractional fungicidal concentration indices; FICI, fractional inhibitory concentration indices; Glr1, glutathione reductase; Gsh1, γ-glutamylcysteine synthetase; LAMB, liposomal amphotericin B; MFC, minimum fungicidal concentration; MIC, minimum inhibitory concentration; Mn-SOD, mitochondrial superoxide dismutase; SG, synthetic glucose; Sod, superoxide dismutase; Sod1, cytosolic superoxide dismutase; Sod2, mitochondrial superoxide dismutase; Trx2, thioredoxin; WT, wild type; Ycf1, glutathione S-conjugate pump
We tested the hypothesis that benzaldehydes could act as Amphotericin B, diamide, 2,3- or 2,5-DHBA, trans-cinnamaldehyde, chemosensitizing agents to AMB against clinical strains and and 3,5-DMBA were procured from Sigma Co
Summary
There has been a persistent effort to improve efficacy of conventional antimycotic drugs, especially for treatment of human candidiasis and cryptococcosis. Liposomal amphotericin B (LAMB), AMB lipid complex, etc., are preferred for clinical therapy of these mycoses, in that conventional AMB (e.g., AMB deoxycholate) is hepatotoxic/nephrotoxic (Patel et al, 2011). Aspergillus terreus, a causative agent of human invasive aspergillosis, is intrinsically resistant to AMB, compared to other aspergilli. This resistance was thought to result from lower membrane ergosterol, offering fewer target sites for AMB (Walsh et al, 2003). This resistance was later found to result from www.frontiersin.org
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
