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Enhancement of antimycotic activity of amphotericin B by targeting the oxidative stress response of Candida and cryptococcus with natural dihydroxybenzaldehydes.

Kim JH, Faria NC, Martins Mde L, Chan KL, Campbell BC - Front Microbiol (2012)

Bottom Line: Some redox-potent chemosensitizers and AMB perturb common cellular targets, resulting in synergistic inhibition of fungal growth.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).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.

View Article: PubMed Central - PubMed

Affiliation: Plant Mycotoxin Research Unit, Western Regional Research Center, Agricultural Research Service, United States Department of Agriculture Albany, CA, USA.

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.

No MeSH data available.


Related in: MedlinePlus

Dilution bioassays showing phenotypic responses of yeast pathogens to amphotericin B (AMB) or diamide. 1 × 106 cells were serially diluted 10-fold in SG liquid medium, and were inoculated onto agar plates. Data are representative results shown from 1 μg mL−1 (AMB) and 0.8 mM (diamide), respectively.
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Figure 1: Dilution bioassays showing phenotypic responses of yeast pathogens to amphotericin B (AMB) or diamide. 1 × 106 cells were serially diluted 10-fold in SG liquid medium, and were inoculated onto agar plates. Data are representative results shown from 1 μg mL−1 (AMB) and 0.8 mM (diamide), respectively.

Mentions: We tested the hypothesis that benzaldehydes could act as chemosensitizing agents to AMB against clinical strains and species of Candida and C. neoformans. First, Petri plate-based yeast dilution bioassays were used to evaluate any relationship between AMB-sensitivity and lower antioxidant capacity. Duplicate assays were performed on SG agar containing AMB (0.0, 0.5, and 1.0 μg mL−1) according to described protocols (Kim et al., 2008). In this test, C. albicans CAN276 was the most sensitive of all strains when exposed up to 1.0 μg mL−1 AMB (Figure 1). Next, we examined the effect of diamide (0.0, 0.2, 0.4, 0.6, and 0.8 mM) on these strains. Diamide causes stoichiometric oxidative stress by depleting cellular thiols, such as glutathione. CAN276 was also the most sensitive of Candida species or strains to diamide (up to 0.8 mM; Figure 1). C. krusei 6258, C. krusei CAN75, and C. tropicalis CAN286 grew similar to control (no diamide) cohorts (i.e., no antifungal activity against these strains at the given concentration). C. albicans 90028 and C. neoformans CN24 showed slight sensitivity to diamide, >100-fold less than CAN276 (Figure 1). The high sensitivity of CAN276 to both AMB and diamide indicated a diminished oxidative stress response system increases sensitivity to AMB.


Enhancement of antimycotic activity of amphotericin B by targeting the oxidative stress response of Candida and cryptococcus with natural dihydroxybenzaldehydes.

Kim JH, Faria NC, Martins Mde L, Chan KL, Campbell BC - Front Microbiol (2012)

Dilution bioassays showing phenotypic responses of yeast pathogens to amphotericin B (AMB) or diamide. 1 × 106 cells were serially diluted 10-fold in SG liquid medium, and were inoculated onto agar plates. Data are representative results shown from 1 μg mL−1 (AMB) and 0.8 mM (diamide), respectively.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3400132&req=5

Figure 1: Dilution bioassays showing phenotypic responses of yeast pathogens to amphotericin B (AMB) or diamide. 1 × 106 cells were serially diluted 10-fold in SG liquid medium, and were inoculated onto agar plates. Data are representative results shown from 1 μg mL−1 (AMB) and 0.8 mM (diamide), respectively.
Mentions: We tested the hypothesis that benzaldehydes could act as chemosensitizing agents to AMB against clinical strains and species of Candida and C. neoformans. First, Petri plate-based yeast dilution bioassays were used to evaluate any relationship between AMB-sensitivity and lower antioxidant capacity. Duplicate assays were performed on SG agar containing AMB (0.0, 0.5, and 1.0 μg mL−1) according to described protocols (Kim et al., 2008). In this test, C. albicans CAN276 was the most sensitive of all strains when exposed up to 1.0 μg mL−1 AMB (Figure 1). Next, we examined the effect of diamide (0.0, 0.2, 0.4, 0.6, and 0.8 mM) on these strains. Diamide causes stoichiometric oxidative stress by depleting cellular thiols, such as glutathione. CAN276 was also the most sensitive of Candida species or strains to diamide (up to 0.8 mM; Figure 1). C. krusei 6258, C. krusei CAN75, and C. tropicalis CAN286 grew similar to control (no diamide) cohorts (i.e., no antifungal activity against these strains at the given concentration). C. albicans 90028 and C. neoformans CN24 showed slight sensitivity to diamide, >100-fold less than CAN276 (Figure 1). The high sensitivity of CAN276 to both AMB and diamide indicated a diminished oxidative stress response system increases sensitivity to AMB.

Bottom Line: Some redox-potent chemosensitizers and AMB perturb common cellular targets, resulting in synergistic inhibition of fungal growth.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).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.

View Article: PubMed Central - PubMed

Affiliation: Plant Mycotoxin Research Unit, Western Regional Research Center, Agricultural Research Service, United States Department of Agriculture Albany, CA, USA.

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.

No MeSH data available.


Related in: MedlinePlus