Inhibition of Fungal Biofilms - Antibiofilm Agents: From Diagnosis to Treatment and Prevention - page 270

communities show intrinsic resistance to azole derivatives, as well as displaying
high levels of resistance against polyenes (Chandra et al. 2001 ; Ramage
et al. 2001a , b ). On the other hand, echinocandins seemed to be active against
biofilms (Bachmann et al. 2002 ; Kuhn et al. 2002 ; Ramage et al. 2002c ).
From the clinical perspective, the most salient feature of fungal biofilms is their
high levels of resistance to most conventional antifungal agents (Ramage
et al. 2012 ). The current consensus is that fungal biofilm resistance is a complex
phenomenon that cannot be explained by one mechanism alone; instead, it is
multifactorial in nature and may involve distinct molecular mechanisms of resis-
tance as compared to those displayed by planktonic cells. Potential contributory
mechanisms to fungal biofilm resistance include: (1) the increased cellular density
of fungal cells within the biofilm, basically a simple concept of “safety in numbers,”
as elegantly demonstrated by the Chaffin group (Perumal et al. 2007 ); (2) the
existence of subpopulations of “persister” cells, dormant variants of regular cells
that form stochastically in microbial populations and are highly tolerant to antifun-
gal treatment and associated with tolerance and chronic infection (LaFleur
et al. 2006 ; Lafleur et al. 2010 ); (3) differences in the metabolic and physiological
status of cells (Baillie and Douglas 1998a , b ); (4) the distinct sterol composition of
the cell wall membrane of sessile as compared to planktonic cells, in particular
decreased ergosterol levels, which may impact amphotericin B activity; (5) the
protective effect of the biofilm matrix, most notably glucans in the Candida biofilm
matrix with the ability to bind azole derivative and also polyenes (Al-Fattani and
Douglas 2006 ; Nett et al. 2007 ; Nobile et al. 2009 ); (6) the upregulation of efflux
pumps, which may occur physiologically during the biofilm mode of growth as a
means to facilitate the removal of toxic products, but may concomitantly result in
increased efflux of antifungal molecules (Mukherjee et al. 2003 ; Ramage
et al. 2002a ); (7) a highly regulated network orchestrated by the hsp90 molecular
chaperone, also with connections to the calcineurin pathway (Robbins et al. 2011 ).
For an excellent, contemporary, and comprehensive review on the topic of biofilm
antifungal drug resistance please refer to Ramage et al. ( 2012 ).

4 Inhibition of Fungal Biofilms

The high morbidity and mortality rates associated with fungal biofilm infections
clearly indicate an urgent and unmet need to develop novel strategies, both pre-
ventative (i.e., inhibition of biofilm formation) and therapeutic (i.e., against
preformed biofilms), to control fungal biofilms in clinical settings, and this is
certainly an area of active research. Much of this work has been facilitated not
only by our increasing understanding of mechanisms involved in fungal biofilm
development at the cellular and molecular level but also by lessons learned during
the clinical management of patients (Nobile et al. 2012 ; Nobile and Mitchell 2006 ;
Ramage et al. 2009 , 2012 ).