Antifungal Drug Discovery through the Study of Invertebrate Model Hosts

Abstract

There is an urgent need for new antifungal agents that are both effective and non-toxic in the therapy of systemic mycoses. The model nematode Caenorhabditis elegans has been used both to elucidate evolutionarily conserved components of host-pathogen interactions and to screen large chemical libraries for novel antimicrobial compounds. Here we review the use of C. elegans models in drug discovery and discuss caffeic acid phenethyl ester, a novel antifungal agent identified using an in vivo screening system. C. elegans bioassays allow high-throughput screens of chemical libraries in vivo. This whole-animal system may enable the identification of compounds that modulate immune responses or affect fungal virulence factors that are only expressed during infection. In addition, compounds can be simultaneously screened for antifungal efficacy and toxicity, which may overcome one of the main obstacles in current antimicrobial discovery. A pilot screen for antifungal compounds using this novel C. elegans system identified 15 compounds that prolonged survival of nematodes infected with the medically important human pathogen Candida albicans. One of these compounds, caffeic acid phenethyl ester (CAPE), was an effective antifungal agent in a murine model of systemic candidiasis and had in vitro activity against several fungal species. Interestingly, CAPE is a potent immunomodulator in mammals with several distinct mechanisms of action. The identification of CAPE in a C. elegans screen supports the hypothesis that this model can identify compounds with both antifungal and host immunomodulatory activity.

Overcoming antifungal resistance

“…In this model Caenorhabditis elegans infected with C. albicans were tested against a drug library in a high-throughput fashion [45]. This model has advantages of identifying effect of candidates on fungal viability, virulence, toxicity and host-elicited immune response.…”

The antifungal effect of peptides from hymenoptera venom and their analogs

“…Candida most readily colonises the skin around the nails or the soft, moist areas around body openings. Candidiasis (also called candidosis or moniliasis) is usually a mild, superficial fungal infection; more rarely Candida enters the bloodstream, and invades the kidneys, lungs, endocardium, brain, or other organs, causing serious infections [1][2][3][4][5]. In addition to the increased occurrence of Candida species infections, resistance against used antifungal agents is increasing.…”

The Drosophila Toll Pathway Controls but Does Not Clear Candida glabrata Infections

“…Invertebrates provide interesting alternative models to study microbial virulence factors and host immune responses (15,16). Drosophila melanogaster, a small fly that is easy to rear, benefits from a century of genetic investigations.…”