Brilacidin, a novel antifungal agent against Cryptococcus neoformans
Camila Diehl,
Camila Figueiredo Pinzan,
Patrícia Alves de Castro,
Endrews Delbaje,
Laura C. García Carnero,
Eddy Sánchez-León,
Kabir Bhalla,
James W. Kronstad,
Dong-gyu Kim,
Tamara L. Doering,
Sondus Alkhazraji,
Nagendra N. Mishra,
Ashraf S. Ibrahim,
Mami Yoshimura,
Luis Alberto Vega Isuhuaylas,
Lien Thi Kim Pham,
Yoko Yashiroda,
Charles Boone,
Thaila Fernanda dos Reis,
Gustavo H. Goldman
Affiliations
Camila Diehl
Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil
Camila Figueiredo Pinzan
Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil
Patrícia Alves de Castro
Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil
Endrews Delbaje
Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil
Laura C. García Carnero
Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil
Eddy Sánchez-León
Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, Canada
Kabir Bhalla
Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, Canada
James W. Kronstad
Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, Canada
Dong-gyu Kim
Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, USA
Tamara L. Doering
Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, USA
Sondus Alkhazraji
Division of Infectious Diseases, The Lundquist Institute for Biomedical Innovation at Harbor-University of California Los Angeles (UCLA) Medical Center, Torrance, California, USA
Nagendra N. Mishra
Division of Infectious Diseases, The Lundquist Institute for Biomedical Innovation at Harbor-University of California Los Angeles (UCLA) Medical Center, Torrance, California, USA
Ashraf S. Ibrahim
Division of Infectious Diseases, The Lundquist Institute for Biomedical Innovation at Harbor-University of California Los Angeles (UCLA) Medical Center, Torrance, California, USA
Mami Yoshimura
RIKEN Center for Sustainable Resource Science, Wako, Saitama, Japan
Luis Alberto Vega Isuhuaylas
Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
Lien Thi Kim Pham
RIKEN Center for Sustainable Resource Science, Wako, Saitama, Japan
Yoko Yashiroda
RIKEN Center for Sustainable Resource Science, Wako, Saitama, Japan
Charles Boone
RIKEN Center for Sustainable Resource Science, Wako, Saitama, Japan
Thaila Fernanda dos Reis
Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil
Gustavo H. Goldman
Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil
ABSTRACT Cryptococcus neoformans causes 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 against C. neoformans. 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 Saccharomyces cerevisiae by analyzing libraries of mutants grown in the presence of BRI. In S. cerevisiae, BRI also affects the cell membrane organization, but in addition the cell wall integrity pathway and calcium metabolism. In vivo experiments show BRI significantly reduces C. neoformans survival inside macrophages and partially clears C. neoformans 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 C. 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 neoformans and Cryptococcus 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 against C. 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 of C. 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 against C. neoformans. We propose BRI as a new antifungal agent against cryptococcosis.
