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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 against\n                      <jats:italic>C. neoformans<\/jats:italic>\n                      . BRI can affect the organization of the cell membrane, increasing the fungal cell permeability. We also investigated the effects of BRI against the model system\n                      <jats:italic>Saccharomyces cerevisiae<\/jats:italic>\n                      by analyzing libraries of mutants grown in the presence of BRI. In\n                      <jats:italic>S. cerevisiae<\/jats:italic>\n                      , BRI also affects the cell membrane organization, but in addition the cell wall integrity pathway and calcium metabolism.\n                      <jats:italic>In vivo<\/jats:italic>\n                      experiments show BRI significantly reduces\n                      <jats:italic>C. neoformans<\/jats:italic>\n                      survival inside macrophages and partially clears\n                      <jats:italic>C. neoformans<\/jats:italic>\n                      lung 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 against\n                      <jats:italic>C. neoformans<\/jats:italic>\n                      . BRI + CAS affects endocytic movement, calcineurin, and mitogen-activated protein kinases. Our results indicate that BRI is a novel antifungal drug against cryptococcosis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>IMPORTANCE<\/jats:title>\n                    <jats:p>\n                      Invasive 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,\n                      <jats:italic>Cryptococcus neoformans<\/jats:italic>\n                      and\n                      <jats:italic>Cryptococcus gattii<\/jats:italic>\n                      . 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 against\n                      <jats:italic>C. neoformans<\/jats:italic>\n                      . 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 of\n                      <jats:italic>C. neoformans<\/jats:italic>\n                      , 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 against\n                      <jats:italic>C. neoformans<\/jats:italic>\n                      . We propose BRI as a new antifungal agent against cryptococcosis.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/mbio.01031-24","type":"journal-article","created":{"date-parts":[[2024,6,25]],"date-time":"2024-06-25T09:00:16Z","timestamp":1719306016000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":20,"title":["Brilacidin, a novel antifungal agent against\n                    <i>Cryptococcus neoformans<\/i>"],"prefix":"10.1128","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3174-0346","authenticated-orcid":false,"given":"Camila","family":"Diehl","sequence":"first","affiliation":[{"name":"Faculdade de Ci\u00eancias Farmac\u00eauticas de Ribeir\u00e3o Preto, Universidade de S\u00e3o Paulo, Ribeir\u00e3o Preto, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camila 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