Synergism of Antifungal Activity between Mitochondrial Respiration Inhibitors and Kojic Acid
Abstract
:1. Introduction
Fungal strains | Strain characteristics | Source/Reference | |
---|---|---|---|
Aspergillus (Human pathogens) | |||
A. fumigatus MYA-3626 | Aspergillosis, Reference clinical strain | ATCC a | |
A. fumigatus AF293 | Aspergillosis, Reference clinical strain | SCVMC b | |
A. fumigatus AF10 | Aspergillosis, Reference clinical strain | SCVMC b | |
A. fumigatus 94-46 | Aspergillosis, Clinical isolate | SCVMC b | |
A. fumigatus 92-245 | Aspergillosis, Clinical isolate | SCVMC b | |
A. terreus UAB673 | Aspergillosis, Clinical isolate | CDC c | |
A. terreus UAB680 | Aspergillosis, Clinical isolate | CDC c | |
A. terreus UAB698 | Aspergillosis, Clinical isolate | CDC c | |
Other filamentous fungi (Human pathogens) | |||
Acremonium sp. CIMR 95-103 | Clinical isolate | SCVMC b | |
Scedosporium sp. CIMR 09-246 | Clinical isolate | SCVMC b | |
Aspergillus (Plant pathogens, etc.) | |||
A. flavus 4212 g | Kojic acid producer, Plant pathogen, Human pathogen (aspergillosis) | NRRL d | |
A. parasiticus 2999 | Kojic acid producer, Plant pathogen | NRRL d | |
A. oryzae A815 | Research strain (model) | FGSC e | |
A. niger 326 | Plant pathogen | NRRL d | |
A. ochraceous 5175 | Plant pathogen | NRRL d | |
A. nidulans A4 | Research strain (model) | FGSC e | |
Penicillium (Plant pathogens, etc.) | |||
P. expansum 974 | Plant pathogen | NRRL d | |
P. expansum W1 | Plant pathogen | [ 26] | |
P. expansum FR2 | Plant pathogen, Fludioxonil resistant (FLUDR) mutant derived from P. expansum W1 | [ 26] | |
P. expansum W2 | Plant pathogen | [ 26] | |
P. expansum FR3 | Plant pathogen, FLUDR mutant derived from P. expansum W2 | [ 26] | |
P. chrysogenum 824 | Fleming’s penicillin-producing strain | NRRL d | |
P. griseofulvum 2159 | Plant pathogen | NRRL d | |
P. griseofulvum 2300 | Plant pathogen | NRRL d | |
P. digitatum 786 | Plant pathogen | NRRL d | |
P. italicum 983 | Plant pathogen | NRRL d | |
P. glabrum 766 | Plant pathogen | NRRL d | |
Yeasts | |||
Saccharomyces cerevisiae BY4741 | Model yeast, Parental strain (Mat a his3∆1 leu2∆0 met15∆0 ura3∆0) | SGD f | |
S. cerevisiae yap1 | Transcription factor Yap1p mutant derived from BY4741 | SGD f | |
S. cerevisiae sod2 | Mitochondrial superoxide dismutase (Mn-SOD) mutant derived from BY4741 | SGD f | |
S. cerevisiae sod1 | Cytosolic superoxide dismutase (Cu,Zn-SOD) mutant derived from BY4741 | SGD f | |
S. cerevisiae glr1 | Glutathione reductase (Glr1p) mutant derived from BY4741 | SGD f |
2. Results and Discussion
2.1. Enhancing Antifungal Activity of H2O2 or Complex III Inhibitors with KA Against Aspergillus or Penicillium Strains: Agar Plate Bioassay
2.1.1. Filamentous Fungi
Strains | H2O2 | Kre-Me | PCS | AntA |
---|---|---|---|---|
Human pathogens | ||||
A. fumigatus MYA-3626 | ++ | + | ++ | + |
A. fumigatus AF293 | + b | + | ++ | + |
A. fumigatus AF10 | ++ | + | ++ | + |
A. fumigatus 94-46 | + | + | ++ | + |
A. fumigatus 92-245 | + | + | ++ | + |
A. terreus UAB673 | ++ b | + | ++ | - |
A. terreus UAB680 | + b | + | ++ | - |
A. terreus UAB698 | ++ b | - | - | - |
Acremonium sp. 95-103 | ++ | ++ | n/t c | ++ |
Scedosporium sp. 09-246 | + | ++ | n/t c | ++ |
Penicillium strains | ||||
P. expansum 974 | ++ | - | - | - |
P. expansum W1 | + | - | - | - |
P. expansum FR2 | + | - | ++ | - |
P. expansum W2 | ++ | - | - | - |
P. expansum FR3 | ++ | - | + | - |
P. chrysogenum 824 | ++ | - | - | - |
P. griseofulvum 2159 | ++ | - | - | - |
P. griseofulvum 2300 | - | - | - | - |
P. digitatum 786 | ++ | n/t d | n/t c | + |
P. italicum 983 | - | + | ++ | - |
P. glabrum 766 | - | + | + | + |
Other Aspergillus strains | ||||
A. flavus 4212 | - | - | - | - |
A. parasiticus 2999 | - | - | - | - |
A. oryzae A815 | - | - | - | - |
A. niger 326 | - | - | - | - |
A. ochraceous 5175 | - | - | - | - |
A. nidulans A4 | - | + | + | - |
2.1.2. Antioxidant, but Not Antifungal, Effect of KA in Wild Type and Antioxidant Mutants of the Model Yeast Saccharomyces cerevisiae
2.2. Calculating Levels of Compound Interactions by Using Microtiter Plate (Microdilution) Bioassays: Human Pathogens, Penicillium Strains or A. nidulans
2.2.1. Co-Application of KA and PCS
Strains (Human pathogens and A. nidulans) | Compounds | MIC alone | MIC combined | FICI |
A. fumigatus AF293 | KA | 64 | 16 | 0.3 |
PCS | >16 b | 1 | ||
A. fumigatus MYA-3626 | KA | >64 c | 16 | 0.4 |
PCS | >16 | 8 | ||
A. fumigatus AF10 | KA | 64 | 16 | 0.4 |
PCS | >16 | 4 | ||
A. fumigatus 92-245 | KA | >64 | 16 | 0.4 |
PCS | >16 | 8 | ||
A. fumigatus 94-46 | KA | >64 | 16 | 0.4 |
PCS | >16 | 8 | ||
A. terreus UAB673 | KA | 64 | 8 | 0.1 |
PCS | >16 | 0.5 | ||
A. terreus UAB 680 | KA | 64 | 8 | 0.2 |
PCS | >16 | 1 | ||
A. nidulans A4 | KA | >64 | 32 | 0.5 |
PCS | >16 | 8 | ||
Acremonium sp. 95-103 | KA | 64 | 16 | 0.8 |
PCS | 0.25 | 0.125 | ||
Scedosporium sp. 09-246 | KA | 64 | 4 | 0.2 |
PCS | 1 | 0.125 | ||
Mean | KA | 89.6 | 14.8 | 0.3 |
PCS | 25.7 | 3.9 | ||
t-test d | KA | - | p < 0.005 | - |
PCS | - | p < 0.005 | - | |
Strains (Human pathogens and A. nidulans) | Compounds | MFC alone | MFC combined | FFCI |
Acremonium sp. 95-103 | KA | >64 | 32 | 0.5 |
PCS | 2 | 0.5 | ||
All other strains | KA | >64 | >64 | 2 |
PCS | >16 | >16 | ||
Mean | KA | 128 | 118.4 | 1.9 |
PCS | 29 | 28.9 | ||
t-test | KA | - | p < 0.5 | - |
PCS | - | p < 1.0 | - | |
Strains (Penicillium strains) | Compounds | MIC alone | MIC combined | FICI |
P. expansum FR2 | KA | >64 | 16 | 0.4 |
PCS | 2 | 0.5 | ||
P. expansum FR3 | KA | >64 | 32 | 0.8 |
PCS | 2 | 1 | ||
P. glabrum 766 | KA | >64 | 32 | 0.4 |
PCS | >16 | 4 | ||
P. digitatum 786 | KA | >64 | 2 | 0.5 |
PCS | 0.25 | 0.125 | ||
P. italicum 983 | KA | >64 | 16 | 0.3 |
PCS | >16 | 4 | ||
Mean | KA | 128 | 19.6 | 0.3 |
PCS | 13.7 | 1.9 | ||
t-test | KA | - | p < 0.005 | - |
PCS | - | p < 0.5 | - | |
Strains (Penicillium strains) | Compounds | MFC alone | MFC combined | FFCI |
P. glabrum 766 | KA | >64 | 64 | 1 |
PCS | >16 | 16 | (99.8%) | |
P. italicum 983 | KA | >64 | 64 | 1 |
PCS | >16 | 16 | (99.8%) | |
All other strains | KA | >64 | > 64 | 2 |
PCS | >16 | >16 | ||
Mean | KA | 128 | 102.4 | 1.6 |
PCS | 32 | 25.6 | ||
t-test | KA | - | p < 0.5 | - |
PCS | - | p < 0.5 | - |
2.2.2. Strains Hypersensitive to Complex III Inhibitors: Testing Acremonium, Scedosporium, P. digitatum with Kre-Me
Strains | Compounds | MIC alone | MIC combined | FICI |
Acremonium sp. 95-103 | KA | 64 | 8 | 0.2 |
Kre-Me | 16 | 1 | ||
Scedosporium sp. 09-246 | KA | 64 | 8 | 0.2 |
Kre-Me | >16 b | 1 | ||
P. digitatum 786 | KA | >64 c | 8 | 0.1 |
Kre-Me | 8 | 0.5 | ||
Mean | KA | 85.3 | 8 | 0.1 |
Kre-Me | 18.7 | 0.8 | ||
t-test d | KA | - | p < 0.05 | - |
Kre-Me | - | p < 0.1 | - | |
Strains | Compounds | MFC alone | MFC combined | FFCI |
Acremonium sp. 95-103 | KA | >64 | 64 | 0.6 |
Kre-Me | >16 | 2 | ||
Scedosporium sp. 09-246 & P. digitatum 786 | KA | >64 | >64 | 2 |
Kre-Me | >16 | >16 | ||
Mean | KA | 128 | 106.7 | 1.5 |
Kre-Me | 32 | 22 | ||
t-test d | KA | - | p < 0.5 | - |
Kre-Me | - | p < 0.5 | - |
Fungal strains | Agents co-applied | |
---|---|---|
PCS (FICI, FFCI) a | Kre-Me (FICI, FFCI) a | |
Human pathogens | ||
A. fumigatus AF293 | (0.3, 2.0) | nt b |
A. fumigatus MYA-3626 | (0.4, 2.0) | nt |
A. fumigatus AF10 | (0.4, 2.0) | nt |
A. fumigatus 92-245 | (0.4, 2.0) | nt |
A. fumigatus 94-46 | (0.4, 2.0) | nt |
A. terreus UAB673 | (0.1, 2.0) | nt |
A. terreus UAB680 | (0.2, 2.0) | nt |
Acremonium sp. 95-103 | (0.8, 0.5) | (0.2, 0.6) |
Scedosporium sp. 09-246 | (0.2, 2.0) | (0.2, 2.0) |
Plant pathogens | ||
P. expansum FR2 | (0.4, 2.0) | nt |
P. expansum FR3 | (0.8, 2.0) | nt |
P. glabrum 766 | (0.4, 1.0) | nt |
P. italicum 983 | (0.3, 1.0) | nt |
P. digitatum 786 | (0.5, 2.0) | (0.1, 2.0) |
Other Aspergillus | ||
A. nidulans A4 | (0.5, 2.0) | nt |
3. Experimental
3.1. Fungal Strains and Culture Conditions
3.2. Chemicals
3.3. Antifungal Bioassay
3.3.1. Agar Plate Bioassay: Filamentous Fungi
3.3.2. Microtiter Plate (microdilution) Bioassay: Filamentous Fungi
3.3.3. Agar Plate Bioassay: S. cerevisiae
4. Conclusions
Acknowledgments
- Sample Availability: Not available.
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Kim, J.H.; Campbell, B.C.; Chan, K.L.; Mahoney, N.; Haff, R.P. Synergism of Antifungal Activity between Mitochondrial Respiration Inhibitors and Kojic Acid. Molecules 2013, 18, 1564-1581. https://doi.org/10.3390/molecules18021564
Kim JH, Campbell BC, Chan KL, Mahoney N, Haff RP. Synergism of Antifungal Activity between Mitochondrial Respiration Inhibitors and Kojic Acid. Molecules. 2013; 18(2):1564-1581. https://doi.org/10.3390/molecules18021564
Chicago/Turabian StyleKim, Jong H., Bruce C. Campbell, Kathleen L. Chan, Noreen Mahoney, and Ronald P. Haff. 2013. "Synergism of Antifungal Activity between Mitochondrial Respiration Inhibitors and Kojic Acid" Molecules 18, no. 2: 1564-1581. https://doi.org/10.3390/molecules18021564