From Biology to Drug Development: New Approaches to Combat the Threat of Fungal Biofilms

Abstract

Fungal infections constitute a major threat to an escalating number of critically ill patients. Fungi are eukaryotic organisms and, as such, there is a limited armamentarium of antifungal drugs, leading to high mortality rates. Moreover, fungal infections are often associated with the formation of biofilms, which contribute to virulence and further complicate treatment due to the high level of antifungal drug resistance displayed by sessile cells within these microbial communities. Thus, the treatment of fungal infections associated with a biofilm aetiology represents a formidable and unmet clinical challenge. The increasing importance and awareness of fungal biofilms is reflected by the fact that this is now an area of very active research. Studies in the last decade have provided important insights into fungal biofilm biology, physiology and pathology, as well as into the molecular basis of biofilm resistance. Here we discuss how this accumulated knowledge may inform the development of new anti-biofilm strategies and therapeutics that are urgently needed.

An In Vitro Model for Oral Mixed Biofilms of Candida albicans and Streptococcus gordonii in Synthetic Saliva

“…Amphotericin B displayed good activity at high doses (16, 4, 1 μg/ml), although we note that these doses are relatively high and generally considered toxic ( Pierce et al, 2013 ). Preformed fungal biofilms show intrinsic resistance to azoles, and as expected fluconazole (even at suprapharmacological concentrations within the mg/ml range) did not have any effect on pre-formed C. albicans biofilms as previously reported ( Ramage et al, 2001 ; Pierce et al, 2015 ; Figure 6A ). In the case of S. gordonii , we observed increased resistance of the preformed bacterial biofilms against monotherapy with clindamycin as compared to the results for inhibition of biofilm formation (compare Figures 5A and 6A ); although treatment with clindamycin was more effective against biofilms grown in BMM synthetic saliva ( Figure 6A ).…”

“…Similar to other members of the oral human microbiota, C. albicans is able to adapt, live and thrive under the environmental conditions encountered within the oral cavity, where biofilm formation constitutes a major contributing factor to its success as a commensal and opportunistic pathogen ( Gendreau and Loewy, 2011 ; O’Donnell et al, 2015b ). Biofilm formation renders fungal cells inaccessible and resistant to antimicrobial treatment and provides protection against the host’s immune system, and as such the impact of complications caused by biofilms on patient care and well-being emphasizes the significance of this study ( Pierce et al, 2013 , 2015 ).…”

Protocol for Identifying Natural Agents That Selectively Affect Adhesion, Thickness, Architecture, Cellular Phenotypes, Extracellular Matrix, and Human White Blood Cell Impenetrability of Candida albicans Biofilms

“…that assess their effects on biofilm formation (17)(18)(19)(20)(21)(22). The number of studies in which the effects of antimicrobial agents on biofilm preparations have been screened has therefore increased in recent years (19,(23)(24)(25)(26)(27)(28)(29).…”

Plasticity of Candida albicans Biofilms

“…This review does not cover in detail the literature on the signal transduction pathways that regulate gene expression during biofilm formation, the genes that are differentially regulated, or the molecular mechanisms regulating matrix formation or drug resistance, unless that information pertains to the specific aim set forth. The reader is directed to a number of excellent reviews on these subjects, published in the past several years (47)(48)(49)(50)(51)(52)(53)(54)(55).…”