Mechanisms of Drug Resistance in Fungi and Their Significance in Biofilms - Antibiofilm Agents: From Diagnosis to Treatment and Prevention - page 55

4.3 Iron Levels Affect MDR

For its survival in host cells, Candida, like many other pathogens, has also adapted
many complex strategies to scavenge depleted iron from the host environment
(Nyilassi et al. 2005 ). In fact, the availability of iron can serve as a common
adaptive signal for pathogens to induce the expression of virulence traits
(Mekalanos 1992 ). Recent studies have already established a role for iron in
systemic infections, whereby the requirement of a high-affinity iron transporter
(CaFtr1p) for infection in a mouse model was shown (Ramanan and Wang 2000 ).
Similarly, the requirement of a siderophore transporter (Arn1p) for epithelial
invasion (Heymann et al. 2002 ) and iron dependent endothelial cell injury (Fratti
et al. 1998 ) suggests that iron plays a vital role in the virulence of C. albicans. The
role of iron in MDR is well established in mammalian cells, where HIF1 is
activated under low iron concentrations that in turn induce the expression of its
target gene MDR1 (Epsztejn et al. 1999 ).
Iron depletion in C. albicans with bathophenanthrolene disulfonic acid and
ferrozine as chelators enhanced its susceptibility to FLC and several drugs (Prasad
et al. 2006 ). Several other species of Candida also display increased sensitivity to
FLC because of iron restriction. Iron uptake mutants, namely ftr1 and ftr2 , as well
as the copper transporter mutant ccc2 , which affects high-affinity iron uptake in
Candida, showed increased susceptibility to FLC. The effect of iron depletion on
drug sensitivity appeared to be independent of the efflux pump proteins Cdr1p and
Cdr2p. This study showed that iron deprivation led to the lowering of membrane
ergosterol and an increase in membrane fluidity, resulting in enhanced passive
diffusion of drugs. Transcriptome analysis of iron deprived cells showed a connec-
tion between calcineurin signaling and iron homeostatsis. Notably, iron-deprived
cells phenocopy deletion of calcineurin pathway genes by showing susceptibility to
alkaline pH, membrane perturbing agents, and salinity stress (Hameed et al. 2011 ).

5 Biofilms and MDR

Biofilms are complex microbial conglomerates which are predominantly surface
attached and enclosed by a thick layer of polysaccharides, making them extremely
drug resistant and difficult to eradicate (Kumamoto 2002 ; Fanning and Mitchell
2012 ). Using an in vitro model, Mukherjee et al. demonstrated that C. albicans
biofilm formation proceeds in three developmental phases: (1) early phase involv-
ing adhesion of fungal cells, (2) intermediate phase during which the blastospores
coaggregate, proliferate, and produce a carbohydrate-rich extracellular matrix
(ECM), and (3) maturation phase, in which the fungal cells are completely encased
in a thick ECM (Mukherjee et al. 2003 ). Fungal biofilms show an increase in drug
resistance with MIC values ranging from 30- to 2,000-fold higher than their
corresponding planktonic cells, which is also developmental phase dependent