Have we been neglecting fungi in the rational design of antimicrobial biomaterials?

摘要

Introduction: Many strategies have been proposed in the development of antimicrobial surface coatings for biomaterials but are these well designed enough to succeed at eliminating both bacterial and fungal infections while being non-cytotoxic? Biofilms from fungal yeasts are in the top three of causative agents in device related infections and yet specific strategies for eliminating fungal biofilms or mixed bacterial and fungal polymicrobial biofilms are lacking. The cellular makeup of fungal cells is distinct from bacterial ones and will therefore necessitate targeting of fungi-specific structures and pathways. Additionally, as eukaryotic pathogens, effective strategies for eliminating fungal biofilms while achieving compatibility with human (also eukaryotic) cell types remains a challenge. We hypothesize that clinically-approved and novel antifungal drugs will become effective antifungal surface formulations when engineered into biomaterial surface coatings and designed to effectively interface with targets within the fungal cell envelope. This will lead to the selective elimination of fungal pathogens (over mammalian cells) during colonisation and prevent the first step in biofilm formation. Materials and Methods: We have developed a method for surface attaching antifungal drugs from the drug classes of echinocandins and polyenes onto model biomaterial surfaces. Their physical properties and mode of attachment have been characterized through extensive surface analysis. The antifungal ability of these materials has been evaluated using three different bioassays, for evaluating their contact killing properties and also the prevention of biofilm formation under static and dynamic conditions. Results and Discussion: When echinocandin drugs were covalently attached to surfaces, they were effective in eliminating nearly all potential fungal colonisers and also prevented the establishment of fungal biofilms on surfaces. These drugs therefore display a new mechanism of action which is mediated by the surface and is related to the cell wall breakdown and likely tied to the processes of yeast cell attachment and species-specific virulence strategies. Polyenes require different attachment and delivery strategies in order interact with their drug target present in the cell membrane. Conclusion: We have begun to understand and describe the design rules needed to fabricate antifungal surface coatings and have now applied these to prototype biomaterials. We see these rules as being compatible with a larger platform technology enabling the effective delivery of antibacterial and antifungal agents while preserving mammalian cell compatibility. These candidate biomaterials will be a step towards addressing the need for clinically-relevant, anti-infective coatings that prevent the establishment of polymicrobial biofilms.