Combinatorial drug approaches to tackle Candida albicans biofilms

Abstract

The human fungal opportunistic pathogen Candida albicans resides in the human gut, genitourinary tract and on the skin. The majority of infections caused by C. albicans are biofilm-related. In the first part of this review, we discuss new insights into C. albicans biofilm characteristics, concentrating on the extracellular matrix, phenotypic switching, efflux pumps and persister cells. It is widely accepted that this multicellular lifestyle is more resistant to traditional antifungal treatment compared to free-living cells. Therefore, much effort is put in the search for combinations of drugs leading to synergistic interactions against microbial biofilms to achieve lower effective doses of the drugs. In the second part of this manuscript, we review all recently identified compounds that act synergistically with azoles, echinocandins and/or polyenes against C. albicans biofilms.

Keywords:

• azole
• biofilm
• Candida albicans
• combination therapy
• echinocandin
• efflux pump
• extracellular matrix
• persister
• phenotypic switching
• polyene
• synergy

Financial and competing interests disclosure

This work was supported by the European Commission’s seventh Framework Programme (FP7/2007–2013) under the grant agreement COATIM (Project no. 278425), the Industrial Research Fund (IOF) of KU Leuven (knowledge platform IOF/KP/11/007) and Agentschap voor Innovatie door Wetenschap en Techniek (IWT Vlaanderen, Belgium) [SBO 120005]. K Thevissen acknowledges the receipt of a postdoctoral fellowship from the Industrial Research Fund (IOFM/05/022) and N Delattin was supported by a postdoctoral mandate grant (PDMK/14/145), both KU Leuven funding. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• The majority of C. albicans infections are biofilm-related.

• Candida albicans biofilm cells display increased resistance towards most available antifungal agents, compared to planktonically growing cells.

• Resistance and virulence of C. albicans biofilms are caused by several factors, including the presence of a multipolymeric extracellular matrix, a small fraction of highly tolerant persister cells, a variety of drug efflux pumps and the species’ ability for phenotypic switching between white, gray and opaque cells.

• The use of antifungal combination therapy, aiming at synergistic action of both compounds, may overcome resistance associated with the biofilm lifestyle and lead to lower dosing regimens of existing antifungals.

• A diversity of compounds acts synergistically with existing antifungal compounds against fungal biofilms. These include natural compounds, peptides and many other compounds with very diverse mode of action. Some of them portray a broad-spectrum synergy (effective in combination with different types of antifungals) probably as a consequence of their multifactorial mode of action or in contrast, because they affect a key tolerance mechanism of biofilm cells.

• Promising in vitro obtained results should be translated to in vivo models and ultimately to clinical trials.

• Repositioning libraries are useful tools to identify new potentiators of existing antifungal compounds as they contain compounds with known toxicity profiles, speeding up the clinical trials.

• The use of robust inhibition/eradication thresholds as end point measurement is highly desirable to calculate synergy between compounds.