Combination Therapy to Treat Fungal Biofilm-Based Infections

Abstract

An increasing number of people is affected by fungal biofilm-based infections, which are resistant to the majority of currently-used antifungal drugs. Such infections are often caused by species from the genera Candida, Aspergillus or Cryptococcus. Only a few antifungal drugs, including echinocandins and liposomal formulations of amphotericin B, are available to treat such biofilm-based fungal infections. This review discusses combination therapy as a novel antibiofilm strategy. More specifically, in vitro methods to discover new antibiofilm combinations will be discussed. Furthermore, an overview of the main modes of action of promising antibiofilm combination treatments will be provided as this knowledge may facilitate the optimization of existing antibiofilm combinations or the development of new ones with a similar mode of action.

Keywords: Aspergillus; Candida; Cryptococcus; biofilms; combination treatment; mode of action; potentiator; synergy; tolerance mechanisms; virulence factors.

Figure 1

Schematic representation of a C. albicans cell in a biofilm context. Important virulence factors and cellular components/pathways involved in C. albicans biofilm tolerance are indicated in green and blue, respectively. Fluconazole potentiators are listed with their main modes of action (red arrows), as discussed in this review. Abbreviations: Erg, ergosterol biosynthesis pathway; CaM, calmodulin; CaN, calcineurin; QS, quorum sensing; ECM, extracellular polymer matrix; H, calcium homeostasis in general; PPIs, proton pump inhibitors; Dxm, dexamethasone; CyA, cyclosporine A.