AUTHOR=Jain Tushar , Mishra Pankaj , Kumar Sushil , Panda Gautam , Banerjee Dibyendu 

TITLE=Molecular dissection studies of TAC1, a transcription activator of Candida drug resistance genes of the human pathogenic fungus Candida albicans

JOURNAL=Frontiers in Microbiology

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2023.994873

DOI=10.3389/fmicb.2023.994873

ISSN=1664-302X

ABSTRACT=<p>The up-regulation of ABC transporters Cdr1p and Cdr2p that efflux antifungal azole drugs are a leading cause of Multi-Drug Resistance (MDR) in the white fungus <italic>Candida albicans</italic>. <italic>C. albicans</italic> was reported to infect patients following the recent Covid-19 pandemic after they were given steroids for recovery. Previously, the <italic>TAC1</italic> gene was identified as the transcriptional activator of <italic>Candida</italic> drug resistance genes (<italic>CDR1</italic> and <italic>CDR2</italic>) and has no known human homologs. This makes it a good target for the development of novel antifungals. We, therefore, carried out the molecular dissection study of <italic>TAC1</italic> to understand the functional regulation of the ABC transporter genes (<italic>CDR1</italic> and <italic>CDR2</italic>) under its control. The N-terminal DNA Binding Domain (DBD) of Tac1p interacts with the Drug Responsive Element (DRE) present in the upstream promoter region of <italic>CDR1</italic> and <italic>CDR2</italic> genes of <italic>C. albicans</italic>. The interaction between DBD and DRE recruits Tac1p to the promoter of <italic>CDR</italic> genes. The C-terminal Acidic Activation Domain (AAD) of Tac1p interacts with the TATA box Binding Protein (TBP) and thus recruits TBP to the TATA box of <italic>CDR1</italic> and <italic>CDR2</italic> genes. Taking a cue from a previous study involving a <italic>TAC1</italic> deletion strain that suggested that Tac1p acts as a xenobiotic receptor, in this study, we identified that the Middle Homology Region (MHR) of Tac1p acts as a probable xenobiotic binding domain (XBD) which plays an important role in <italic>Candida</italic> drug resistance. In addition, we studied the role of Tac1p in the regulation of some lipid profiling genes and stress response genes since they also contain the DRE consensus sequence and found that some of them can respond to xenobiotic stimuli.</p>