Molecule Information

General Information of the Molecule (ID: Mol04244)

• Name: Zinc cluster transcription factor Znc1 ,Candida albicans
• Synonyms: Zinc cluster transcription factor Znc1
• Molecule Type: Protein

Kingdom: Fungi
Phylum: Ascomycota
Class: Saccharomycetes
Order: Saccharomycetales
Family: Debaryomycetaceae
Genus: Candida
Species: Candida albicans

Type(s) of Resistant Mechanism of This Molecule

  IDUE: Irregularity in Drug Uptake and Drug Efflux

Drug Resistance Data Categorized by Drug

Approved Drug(s) 1 drug(s) in total

Miltefosine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Disease Class: Fungal infection [ICD-11: 1F29-1F2F] [1]

• Resistant Disease: Fungal infection [ICD-11: 1F29-1F2F]
• Resistant Drug: Miltefosine
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SC5314 cells; N.A.; Homo sapiens (Human); N.A.
• Experiment for Drug Resistance: Susceptibility testing
• Mechanism Description: Activating mutations in the ZCFs Mrr1, Tac1, and Upc2 frequently cause acquired resistance to the widely used antifungal drug fluconazole in the pathogenic yeast?Candida albicans. Similar to a hyperactive Tac1, a constitutively active form of the ZCF Znc1 causes increased fluconazole resistance by upregulating the multidrug efflux pump-encoding gene?CDR1. Hyperactive forms of both Tac1 and Znc1 also cause overexpression of?RTA3, which encodes a seven-transmembrane receptor protein involved in the regulation of asymmetric lipid distribution in the plasma membrane.?RTA3?expression is also upregulated by miltefosine, an antiparasitic drug that is active against fungal pathogens and considered for treatment of invasive candidiasis, and?rta3delta mutants are hypersensitive to miltefosine. We found that activated forms of both Tac1 and Znc1 confer increased miltefosine resistance, which was dependent on?RTA3?whereas?CDR1?was dispensable. Intriguingly, the induction of?RTA3?expression by miltefosine depended on Znc1, but not Tac1, in contrast to the known Tac1-dependent?RTA3?upregulation by fluphenazine. In line with this observation,?znc1delta mutants were hypersensitive to miltefosine, whereas?tac1delta mutants showed wild-type tolerance. Forced expression of?RTA3?reverted the hypersensitivity of?znc1delta mutants, demonstrating that the hypersensitivity was caused by the inability of the mutants to upregulate?RTA3?in response to the drug. These findings establish Znc1 as a key regulator of miltefosine-induced?RTA3?expression that is important for wild-type miltefosine tolerance.

References

• Ref 1: The zinc cluster transcription factor Znc1 regulates Rta3-dependent miltefosine resistance in Candida albicans. mSphere. 2024 Jul 30;9(7):e0027024.