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

Author(s)

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

• Document type: Journal article
• Source: ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY; v. 79, p. 11-pg., 2023-08-01.

Abstract

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)

• FAPESP's process: 21/01279-5 - Investigation of new targets and antifungal molecules on Candida spp. and Cryptococcus spp.
• Grantee: Kelly Ishida
• Support Opportunities: Regular Research Grants
• FAPESP's process: 20/03850-9 - Mycobacterium cell wall: structural studies and inhibition strategies for enzymes involved in the biosynthesis and regulation
• Grantee: Marcio Vinicius Bertacine Dias
• Support Opportunities: Regular Research Grants
• FAPESP's process: 18/11612-0 - Investigation of the antifungal activity and mechanism of action of 2-aryloxazolines derivatives on Candida albicans
• Grantee: Vinicius de Morais Barroso
• Support Opportunities: Scholarships in Brazil - Doctorate