Epigenetic Regulation of Antifungal Drug Resistance
Abstract
:1. Introduction
2. Antifungal Resistance Mechanisms
3. RNA-Based Epigenetic Modifications in Antifungal Resistance
4. Chromatin-Based Epigenetic Modifications in Antifungal Resistance
4.1. Histone-Modifying Enzymes in Antifungal Resistance
4.1.1. Histone Acetyltransferases
4.1.2. Histone Deacetylases
4.1.3. Histone Methyltransferases and Demethylases
4.2. Chromatin-Remodeling Complexes in Antifungal Resistance
5. Role of DNA-Damage Repair Mechanisms in Antifungal Resistance
6. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Acknowledgments
Conflicts of Interest
References
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Antifungal Drug Classes | Target Pathway | Mode of Action | Commonly Used Drugs |
---|---|---|---|
Azoles | Ergosterol biosynthesis | Inhibit the activity of lanosterol 14α-demethylase, encoded by ERG11 and Cyp51 genes | Ketoconazole, fluconazole, voriconazole, itraconazole and posaconazole |
Echinocandins | 1,3 β-glucan biosynthesis | Inhibit the activity of β (1,3)-glucan synthase enzyme, encoded by FKS genes | Caspofungin, micafungin and anidulafungin |
Polyenes | Ergosterol biosynthesis | Extract ergosterol and create pores in the plasma membrane | Amphotericin B, nystatin and natamycin |
Organism | Efflux Pump | Pump Type |
---|---|---|
Candida albicans | CaCdr1 | ABC-T |
CaCdr2 | ABC-T | |
CaMdr1 | MFS-T | |
Candida glabrata | CgCdr1 | ABC-T |
CgCdr2/CgPdh1 | ABC-T | |
CgSnq2 | ABC-T | |
Candida krusei | CkAbc1 | ABC-T |
CkAbc2 | ABC-T | |
Candida tropicalis | CtCdr1 | ABC-T |
Candida auris | CauCdr1 | ABC-T |
CauMdr1 | MFS-T |
Histone Modifier | Reported Candida Species Having Histone Modifier | Modification | Mutant Phenotype towards Antifungal Drugs | References | ||
---|---|---|---|---|---|---|
Azoles | Echinocandins | |||||
Acetyl transferases | Gcn5 | Ca#, Cg# | H3K14 acetylation | Sensitivity in Ca | [17] | |
Hat1 | Ca, Cg | Resistance in Ca | [41] | |||
Rtt109 | Ca, Cg | H3K56 acetylation | Sensitivity in Ca | [45] | ||
Ada2 | Ca, Cg | SAGA complex subunit | Sensitivity in Ca | [17] | ||
Deacetylases | Hos2 * | Ca, Cg | Sensitivity in Ca | [54] | ||
Rpd3 * | Ca, Cg | Sensitivity in Ca | [42,54] | |||
Rpd31 * | Ca | Sensitivity in Ca | [54] | |||
had1 * | Ca, Cg | H3K14 deacetylation | Sensitivity in Ca | [42,54] | ||
Hst1 | Ca, Cg | Resistance in Cg | [57] | |||
Methyl transferases | Set1 | Ca, Cg | H3K4 methylation | Sensitivity in Cg | [62] | |
Set2 | Ca, Cg | H3K36 methylation | Resistance in Cg | [43] | ||
Demethylase | Rph1 | Ca, Cg | Sensitivity in Cg | [43] |
DNA Repair Pathway | Gene Name | Name Description | Candida Species Reported to Mutations | Mutant Phenotype towards Antifungals | ||
---|---|---|---|---|---|---|
Azoles | Echinocandins | Polyenes | ||||
Mismatch repair (MMR) pathway | MSH2 | MutS homolog | Ca, Cg | Fluconazole resistance in Ca and Cg [73,75] | Caspofungin sensitivity in Ca, but caspofungin and micafungin resistance in Cg [73,75,76] | Amphotericin B resistance in Cg [75] |
PMS1 | Post-meiotic segregation | Ca | Fluconazole resistance in Ca [73] | - | - | |
Homologous recombination (HR) pathway | RAD52 | Radiation sensitive | Ca | Fluconazole susceptibility in Ca [73] | - | - |
RAD50 | Radiation sensitive | Ca, Cg | Fluconazole susceptibility in Ca, but resistance in Cg [73,75] | Caspofungin sensitivity in Ca, but resistance in Cg [73,75] | Amphotericin B resistance in Cg [75] | |
MRE11 | Meiotic recombination | Ca | Fluconazole sensitivity in Ca [73] | - | - | |
Non-Homologous End-Joining (NHEJ) pathway | YKU80 | Yeast Ku protein | Ca, Cg | No role in azole resistance in Ca, but increased fluconazole tolerance in Cg [73,74] | No role in caspofungin susceptibility in Cg [74] | - |
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Patra, S.; Raney, M.; Pareek, A.; Kaur, R. Epigenetic Regulation of Antifungal Drug Resistance. J. Fungi 2022, 8, 875. https://doi.org/10.3390/jof8080875
Patra S, Raney M, Pareek A, Kaur R. Epigenetic Regulation of Antifungal Drug Resistance. Journal of Fungi. 2022; 8(8):875. https://doi.org/10.3390/jof8080875
Chicago/Turabian StylePatra, Sandip, Mayur Raney, Aditi Pareek, and Rupinder Kaur. 2022. "Epigenetic Regulation of Antifungal Drug Resistance" Journal of Fungi 8, no. 8: 875. https://doi.org/10.3390/jof8080875