Mechanisms of Drug Resistance in Fungi and Their Significance in Biofilms - Antibiofilm Agents: From Diagnosis to Treatment and Prevention - page 48

(FD) through a transporter rather than by passive diffusion. Other azoles compete
for FLC import, suggesting that all azoles utilize the same FD mechanism. FLC
import was also shown to vary among C. albicans -resistant clinical isolates,
suggesting that altered FD may be a previously uncharacterized mechanism of
resistance to azole drugs (Mansfield et al. 2010 ). However, the identification of a
membrane transporter protein involved in FD of azoles remains elusive (Mansfield
et al. 2010 ). Interestingly, drug inactivation that is a common mechanism in
bacteria has not been observed in Candida cells.
2.5 Drug Efflux
Increased efflux, which leads to reduced intracellular accumulation of drugs, is
another prominent mechanism of MDR in fungi (Prasad and Kapoor 2005 ). In
C. albicans, for example, this is achieved by increasing the efflux of drugs from
cells by overproducing the plasma membrane (PM) efflux pump proteins. An
induction in the expression levels of genes encoding efflux pump proteins, partic-
ularly A TP B inding C assette (ABC) multidrug transporter proteins Cdr1 and Cdr2
or M ajor F acilitator S uperfamily (MFS) efflux pump protein Mdr1, have been
commonly observed in azole-resistant clinical isolates of C. albicans (White
et al. 2002 ; Prasad and Kapoor 2005 ; Karababa et al. 2004 ; Kusch et al. 2004 ).
Invariably, MDR Candida cells, which show enhanced expression of efflux pump
encoding genes, also show simultaneous increase in the efflux of drugs, thus
implying a causal relationship between efflux pump encoding gene expression
levels and intracellular concentration of the drug (Cannon et al. 2009 ).
2.5.1 ABC Transporters
An inventory of C. albicans ABC transporters revealed that there are 28 putative
ABC superfamily members, including 12 half transporters, that largely remain
uncharacterized (Gaur et al. 2005 ). These putative ABC proteins could be grouped
into five “known” subfamilies, including C. albicans Pdr protein (CaPdrp), and a
sixth “others” category that includes soluble ABC non-transporter proteins
unrelated to the existing fungal subfamilies. The Pdr protein subfamily of
C. albicans comprises seven full-size members: Cdr1p, Cdr2p, Cdr3p, Cdr4p,
Cdr11p, CaSnq2p, and Ca4531. The C. albicans Cdr1p and Cdr2p proteins are
active multidrug transporters, while Cdr3p and Cdr4p do not efflux drugs and play
no apparent role in the development of antifungal resistance (Prasad and Goffeau
2012 ). Other transporters in related fungi, including CgCDR1 (Sanglard
et al. 1999 ) , CgCDR2 (PDH1) (Miyazaki et al. 1998 ), and SNQ2 (Torelli
et al. 2008 )in C. glabrata , ABC1 in C. krusei (Katiyar and Edlind 2001 ), and
AFR1 (Sanguinetti et al. 2006 )in C. neoformans, are multidrug transporters and
play a role in the development of MDR in these pathogenic species.