Mechanisms of Drug Resistance in Fungi and Their Significance in Biofilms - Antibiofilm Agents: From Diagnosis to Treatment and Prevention - page 57

in AfMDR4 drug efflux pump gene expression in these biofilms and a subsequent
increase in drug resistance, which could be reversed by the presence of an efflux
pump inhibitor (Rajendran et al. 2011 ).
Several studies show that ECM comprised predominantly of

-1, 3 glucans is
most predominantly linked to antifungal resistance in biofilm. ECM acts as a barrier
which imposes restriction on free diffusion of drugs within the biofilm. Therefore,
the nature and extent of ECM determines the drug diffusion and threshold of
resistance for the particular biofilm community (Seneviratne et al. 2008 ). There
are several studies where glucan levels were linked to MDR of biofilms. For
example, by exploiting FKS1 mutant strains (defective in β -1, 3 glucans synthase),
it was shown that glucan production in the mutant strain was reduced to 60 % to that
of wild-type cells rendering biofilms susceptible to azoles (Nett et al. 2010 ). Sim-
ilarly, HSP90 in addition to having a role in biofilm dispersion has also been linked
to biofilm hyper resistance to antifungals since it also regulates the production of
ECM components (Robbins et al. 2011 ). The presence of ECM has also been shown
to be responsible for the development of persister cells within fungal biofilms.
Persister cells evolve from similar susceptible cells but escape the drug assault by
being located within the biofilm matrix, grow slowly and develop tolerance to drugs
(Lewis 2005 ).
Although, the presence of ECM seems to be the major contributor of MDR in
biofilms, in some cases where ECM is underdeveloped (like early stages of
biofilms), sessile cells grown planktonically still show enhanced drug resistance.
It seems there are several diverse cellular pathways leading to increased drug
resistance in biofilms (Baillie and Douglas 2000 ; Blankenship and Mitchell
2006 ). In most of the tested conditions, no one mechanism of biofilm resistance
was the sole determinant of increased resistance, as each controls specific devel-
opmental stages of biofilm.
In conclusion, all the evidence related to MDR and its mechanism in fungal
cells, including those in biofilms, suggests that it is a multifactorial phenomenon,
where not only MDR efflux pumps but also drug target alteration and transcrip-
tional activation have an active role. Several other factors also contribute to the
development of drug tolerance in fungi, in this context emerging roles of mito-
chondria, CW and lipids in MDR deserve more attention. The blocking of efflux
pumps to expel incoming drugs is a common strategy pursued which has resulted in
the identification of a few select inhibitors and modulators. However, such
approaches, while promising, may not be sufficient to sensitize MDR cells, partic-
ularly when one considers the existence of several efflux proteins which may still be
drug transporters and the contribution of yet unknown factors. Multi-target thera-
peutic strategies would be an ideal comprehensive approach in combating not only
fungal infections but also in preventing the development of MDR.

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