Crystal structure of dihydrofolate reductase from the emerging pathogenic fungus Candida auris

Autor(es)

Kirkman, Tim ; Sketcher, Alice ; Barroso, Vinicius de Morais ; Ishida, Kelly ; Tosin, Manuela ; Bertacine Dias, Marcio Vinicius

• Tipo de documento: Artigo Científico
• Fonte: ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY; v. 79, p. 11-pg., 2023-08-01.

Resumo

Candida auris has emerged as a global health problem with a dramatic spread by nosocomial transmission and a high mortality rate. Antifungal therapy for C. auris infections is currently limited due to widespread resistance to fluconazole and amphotericin B and increasing resistance to the front-line drug echinocandin. Therefore, new treatments are urgently required to combat this pathogen. Dihydrofolate reductase (DHFR) has been validated as a potential drug target for Candida species, although no structure of the C. auris enzyme (CauDHFR) has been reported. Here, crystal structures of CauDHFR are reported as an apoenzyme, as a holoenzyme and in two ternary complexes with pyrimethamine and cycloguanil, which are common antifolates, at near-atomic resolution. Preliminary biochemical and biophysical assays and antifungal susceptibility testing with a variety of classical antifolates were also performed, highlighting the enzyme-inhibition rates and the inhibition of yeast growth. These structural and functional data might provide the basis for a novel drug-discovery campaign against this global threat. (AU)

• Processo FAPESP: 21/01279-5 - Investigação de novos alvos e moléculas antifúngicas sobre Candida spp. e Cryptococcus spp.
• Beneficiário: Kelly Ishida
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 20/03850-9 - Parede celular micobacteriana: estudo estrutural e estratégias de inibição de enzimas relacionadas com sua biossíntese e regulação
• Beneficiário: Marcio Vinicius Bertacine Dias
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 18/11612-0 - Investigação da atividade antifúngica e do mecanismo de ação de derivados 2-ariloxazolinas sobre Candida albicans
• Beneficiário: Vinicius de Morais Barroso
• Modalidade de apoio: Bolsas no Brasil - Doutorado