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Advisor(s)
Abstract(s)
The lack of antifungal drugs with novel modes of action reaching the clinic is a serious
concern. Recently a novel antifungal protein referred to as Blad-containing oligomer
(BCO) has received regulatory approval as an agricultural antifungal agent. Interestingly
its spectrum of antifungal activity includes human pathogens such as Candida albicans,
however, its mode of action has yet to be elucidated. Here we demonstrate that BCO
exerts its antifungal activity through inhibition of metal ion homeostasis which results in
apoptotic cell death in C. albicans. HIP HOP profiling in Saccharomyces cerevisiae using
a panel of signature strains that are characteristic for common modes of action identified
hypersensitivity in yeast lacking the iron-dependent transcription factor Aft1 suggesting
restricted iron uptake as a mode of action. Furthermore, global transcriptome profiling
in C. albicans also identified disruption of metal ion homeostasis as a potential mode of
action. Experiments were carried out to assess the effect of divalent metal ions on the
antifungal activity of BCO revealing that BCO activity is antagonized by metal ions such
as Mn2C, Zn2C, and Fe2C. The transcriptome profile also implicated sterol synthesis
as a possible secondary mode of action which was subsequently confirmed in sterol
synthesis assays in C. albicans. Animal models for toxicity showed that BCO is generally
well tolerated and presents a promising safety profile as a topical applied agent. Given
its potent broad spectrum antifungal activity and novel multitarget mode of action, we
propose BCO as a promising new antifungal agent for the topical treatment of fungal
infections
Description
Original Research
Keywords
blad-containing oligomer antifungal metal chelation metal homeostasis multitarget mode of action toxicology
Pedagogical Context
Citation
Pinheiro AM, Carreira A, Prescott TAK, Ferreira RB and Monteiro SA (2017) Bridging the Gap to Non-toxic Fungal Control: Lupinus-Derived Blad-Containing Oligomer as a Novel Candidate to Combat Human Pathogenic Fungi. Front. Microbiol. 8:1182
Publisher
Miguel Cacho Teixeira (ed.)