Mechanisms of Drug Resistance in Fungi and Their Significance in Biofilms - Antibiofilm Agents: From Diagnosis to Treatment and Prevention - page 52

Table 1 MDR regulators in C. albicans and S. cerevisiae and their target genes
TFs Target genes References

Candida albicans

TAC1 CDR1 , CDR 2, IFU5 , HSP12 , RTA3 , GPX1 , CHK1 , LCB4 ,

NDH2 , SOU1 , etc.

Liu et al. ( 2007 )

MRR1 MDR1 Morschhauser

et al. ( 2007 )

NDT80 CDR1 , ERG genes, MDR1 , CDR2 Sasse et al. ( 2011 )

MCM1 MDR1, EFG1, WOR1, WOR2, CZF1 Tuch et al. ( 2008 )

CAP1 CAP1, GLR1, TRX1, SOD1, CAT1, PDR16, MDR1, FLU1,
YCF1, FCR1

Znaidi et al. ( 2009 )

UPC2 CDR1, MDR1, YOR1, MET6, ERG genes Znaidi et al. ( 2008 )

Saccharomyces cerevisiae

PDR1 PDR5, PDR15, PDR10, SNQ2, YOR1, HXT9, HXT11 Bauer et al. ( 1999 )

PDR3 SNQ2, HXT9, HXT11, PDR5, PDR15, YOR1 Bauer et al. ( 1999 )

YAP1 SNQ2, YCF1 Bauer et al. ( 1999 )

sequence, the pleiotropic drug resistance responsive element (PDRE) used by Pdr1
and Pdr3. Notably, the deletion of their counterparts in Candida neither affected the
drug-induced expression of CDR1, CDR2, and MDR1 nor their level of resistance.
Therefore, the role of these TFs in MDR in Candida is yet to be uncovered (Coste
et al. 2008 ).

4 Novel Mechanisms of MDR

In addition to the well-known mechanisms and circuitry implicated in drug resis-
tance, there are various novel pathways or unconventional mechanisms, which are
emerging as new MDR determinants in Candida cells. Some of these mechanisms
are discussed briefly in the succeeding text (Table 2 ).

4.1 Mitochondria and Cell Wall Integrity Affects Drug
Susceptibility

Protein kinase C (PKC) regulates CW integrity during growth, morphogenesis, and
response to stress. The genetic impairment of Pkc1 confers hypersensitivity to
multiple drugs that target synthesis of the key cell membrane sterol ergosterol,
including azoles, allylamines, and morpholines. Deletion of C. albicans PKC1 in
turn makes fungistatic ergosterol biosynthesis inhibitors fungicidal and attenuates
virulence (LaFayette et al. 2010 ). Notably, Pkc1 enables survival of cell membrane
stress at least in part via the mitogen-activated protein kinase (MAPK) cascade in
S. cerevisiae and C. albicans through distinct downstream effectors. Strikingly,