Mechanisms of Drug Resistance in Fungi and Their Significance in Biofilms - Antibiofilm Agents: From Diagnosis to Treatment and Prevention - page 50

Fig. 2 Predicted topology of MFS drug: H + antiporter involved in drug transport. It has
12 (DHA1) or 14 (DHA2) TMSs and does not contain NBDs, but TMS5 harbors an H + -antiporter
motif, which couples electrochemical gradient of protons to drug transport

C. dubliniensis clinical isolates (Moran et al. 1998 ). Since CgMDR1 confers
specific resistance to FLC, its constitutive expression in C. glabrata may be
responsible for the intrinsically low susceptibility of this yeast species to FLC
(Sanglard et al. 1999 ).
Among all the MFS proteins, only one member, MDR1, has been implicated
clinically to be involved in azole resistance. FLU1 , a close homologue of MDR1 ,
has also been isolated by its ability to confer fluconazole resistance in hypersus-
ceptible S. cerevisiae transformants. However, overexpression of FLU1 has not
been detected in FLC-resistant clinical isolates of C. albicans . None of the other
95 members of this superfamily are implicated in MDR (Gaur et al. 2008 ). As an
important MDR gene of the MFS family, MDR1 has been extensively studied for its
role in drug resistance. The functional evaluation of critical amino acid residues of
the Mdr1 protein revealed that the residues of TMS5 which harbor antiporter motifs
(G(X6)G(X3)GP(X2)GP(X2)G) are potentially significant for their functionality
and contribute to drug: H + transport. Independent of the substrate specificity of the
antiporter, the antiporter motif in the predicted TMS5 is conserved in all of the
functionally related subgroups in bacteria and plants. Multiple-sequence analysis of
the MFS transporters revealed that proteins within this family share greater simi-
larity between their N-terminal halves than their C-terminal halves, and it is
assumed that

the later half is responsible for substrate recognition (Paulsen

et al. 1996 ).