Mechanisms of Drug Resistance in Fungi and Their Significance in Biofilms - Antibiofilm Agents: From Diagnosis to Treatment and Prevention - page 51

3 Regulation of MDR Genes
As discussed above, the MDR strains overexpress two ABC transporter encoding
genes, CDR1 and CDR2 , which are homologous to the pleiotropic drug-resistance
transporter Pdr5 from S. cerevisiae (Coste et al. 2004 ). In C. albicans , FCR1 and
TAC1 were identified as Sc PDR1 - PDR3 homologs. While in S. cerevisiae the
FCR1 gene product behaved as a transcriptional activator, in C. albicans it acted
as a negative regulator (Talibi and Raymond 1999 ). Only Tac1p has been experi-
mentally proven to function as a transcriptional activator of C. albicans drug efflux
transporter genes, such as CDR1 and CDR2 (Coste et al. 2004 ). Most of the MDR
strains present a loss of heterozygocity and/or aneuploidy at the TAC1 locus,
combined to GOF mutations of TAC1 (Coste et al. 2004 ).
Another TF, CaNDT80 , has diverse roles as it controls the expression of not only
CDR genes but of ERG and MDR1 genes as well (Sasse et al. 2011 ). CaNDT80 is
required for constitutive overexpression of the CDR1 and ERG genes but is
dispensable for MDR1 and CDR2 drug-mediated induction, indicating its contribu-
tion in nearly all the predominant mechanisms of drug resistance in C. albicans .
Notably, there was a slight increase in CDR2 expression in CaNDT80 mutants
indicating the gene's repressible nature. The role of CaNDT80 in FLC resistance
was not prominent as CaNDT80 mutant cells were more resistant to FLC than the
wild-type strain (Sasse et al. 2011 ).
Another family of TFs controlling drug transporter genes belongs to bZip family
(Alarco and Raymond 1999 ). C. albicans harbors a homologue of the YAP protein
family designated as Cap1 protein which is involved in oxidative stress and also
regulates expression of genes encoding members of both the MFS and ABC
transporter superfamilies (Alarco and Raymond 1999 ). There is an intricate inter-
play between MRR1 , CAP1, and UPC2 TFs that governs the induction and consti-
tutive overexpression of MDR1 (Schubert et al. 2011 ). Interestingly, a mutation in
MRR1 resulted in the constitutive overexpression of MDR1 even in the absence of
UPC2 or CAP1, whereas a GOF mutation in UPC2 slightly activated MDR1
expression, which was dependent on the presence of MRR1. The activated form
of CAP1 was also partially dependent on MRR1 for expression of MDR1 . On the
other hand, induction of MDR1 by drugs was also shown to be independent of
UPC2 but required MRR1 and was partially dependent on CAP1 (Schubert
et al. 2011 ). In addition to MDR1 , the global regulator UPC2 also regulates other
mediators of MDR such as CDR1 / CDR2 and ergosterol biosynthesis genes includ-
ing the FLC target ERG11 . Yet another TF that has been implicated in the
regulation of MDR1 expression is Mcm1p, a member of the MADS box TF family.
The MDRE/BRE in the MDR1 promoter contains a putative Mcm1p binding site
(Riggle and Kumamoto 2006 ). Table 1 lists some of the known regulators of MDR
genes.
Three additional zinc cluster TFs were identified by Sanglard and coworkers
( CTA4, ASG1 , and CTF1 ) and all complemented the FLC hypersusceptibility of
S. cerevisiae nulls of pdr1 pdr3 and restored PDR5 expression via the cis-acting