Biomedical Engineering Reference
In-Depth Information
(PG) in azole-resistant isolates could be linked to compromised CW integrity and
drug resistance in C
. albicans
cells (Singh et al.
2013
).
Evidence of cross talk between CW and MDR comes from another unrelated
study. RNAseq of an MDR strain and its isogenic drug susceptible counterpart led
to the identification of an upregulated TF encoding gene
CZF1
, which was involved
in hyphal transition and white/opaque switching (Vinces et al.
2006
). Notably,
CZF1
was also co-induced with
CDR1
and
CDR2
in MDR isolates. Interestingly,
the inactivation of
CZF1
increased the resistance of the cells to CW perturbing
agents, through the overexpression of beta glucan synthesis genes. The study
proposed a positive role of
CZF1
on MDR and a negative role on CW integrity
(Dhamgaye et al.
2012a
). The mechanism of cross talk between CW stresses,
mitochondrial dysfunction, and MDR is not completely lucid, but these examples
reiterate their interdependence to mitigate cellular stresses.
4.2 Lipids in MDR
On the basis of several studies, a close interaction between membrane lipids and
drug-extrusion pump proteins has been recognized (Marie and White
2009
). For
example, the drug-extrusion pump proteins, particularly belonging to ABC super-
family, are predominantly localized within microdomains of PM (rafts) and thus are
sensitive to the nature and the physical state of the membrane lipids (Pasrija
et al.
2008
). For example, any imbalance in the main constituents of membrane
rafts, such as sphingolipids or ergosterol levels, result in abrogated functionality of
the drug extrusion pumps (Prasad et al.
2006
). It has also been observed that the
ABC drug-efflux proteins in yeast (Pdr5p and Yor1p in
S. cerevisiae
, and Cdr1p and
Cdr2p in
C. albicans
) can translocate phospholipids between the two monolayers of
the PM (Smriti et al.
2002
).
The adaptation of
C. albicans
to tolerate antifungals is accompanied by many
specific and global changes in lipids (Singh et al.
2013
). Recently, the detailed
lipidomics of several genetically matched (isogenic) as well as select sequential
azole sensitive and resistant clinical isolates of
C. albicans
provided a comprehen-
sive evaluation of lipids as the determinants of drug resistance and showed that each
resistant isolate possessed a characteristic lipid composition. Development of azole
tolerance also impelled the remodeling of molecular species of lipids. The fact that
lipidomic response of match pair isolates was associated with simultaneous
overproduction of efflux pump membrane proteins suggested a possible common
regulatory mechanism between the two phenomena (Singh et al.
2013
). Such a
common link has already been observed in
S. cerevisiae
and
C. glabrata,
where
genes encoding efflux pumps, such as ScPdr5 or CgCdr1 and CgCdr2, play an
important role in regulating lipid levels (Shahi and Moye-Rowley
2009
).
Search WWH ::
Custom Search