Brilacidin, a novel antifungal agent againstCryptococcus neoformans

Abstract

AbstractCryptococcus neoformanscauses cryptococcosis, one of the most prevalent fungal diseases, generally characterized by meningitis. There is a limited and not very effective number of drugs available to combat this disease. In this manuscript, we show the host defense peptide mimetic brilacidin (BRI) as a promising antifungal drug againstC. neoformans. BRI is able to affect the organization of the cell membrane, increasing fungal cell permeability. We also investigated the effects of BRI against the model systemSaccharomyces cerevisiaeby analyzing libraries of mutants grown in the presence of BRI. InS. cerevisiae, BRI also affects the cell membrane organization, but in addition the cell wall integrity pathway and calcium metabolism.In vivoexperiments show BRI significantly reducesC. neoformanssurvival inside macrophages and partially clearsC. neoformanslung infection in an immunocompetent murine model of invasive pulmonary cryptococcosis. We also observed that BRI interacts with caspofungin (CAS) and amphotericin (AmB), potentiating their mechanism of action againstC. neoformans. BRI+CAS affects endocytic movement, calcineurin, and mitogen activated protein kinases. Our results indicate that BRI is a novel antifungal drug against cryptococcosis.ImportanceInvasive fungal infections have a high mortality rate causing more deaths annually than tuberculosis or malaria. Cryptococcosis, one of the most prevalent fungal diseases, is generally characterized by meningitis and is mainly caused by two closely related species of basidiomycetous yeasts,Cryptococcus neoformansandCryptococcus gattii. There are few therapeutic options for treating cryptococcosis and searching for new antifungal agents against this disease is very important. Here, we present brilacidin (BRI) as a potential antifungal agent againstC. neoformans. BRI is a small molecule host defense peptide mimetic that has previously exhibited broad-spectrum immunomodulatory/anti-inflammatory activity against bacteria and viruses. BRI alone was shown to inhibit the growth ofC. neoformans, acting as a fungicidal drug, but surprisingly also potentiated the activity of caspofungin (CAS) against this species. We investigated the mechanism of action of BRI and BRI+CAS againstC. neoformans. We propose BRI as a new antifungal agent against cryptococcosis.