CRISPR-Cas9 approach confirms Calcineurinresponsive zinc finger 1 (Crz1) transcription factor as a promising therapeutic target in echinocandin-resistant Candida glabrata

Andres Ceballos-Garzon, Elvira Roman, Jesús Pla, Fabrice Pagniez, Daniela Amado, Carlos J. Alméciga-Díaz, Patrice Le Pape, Claudia M. Parra-Giraldo

Research output: Contribution to journalResearch Articlepeer-review

6 Scopus citations

Abstract

Invasive fungal infections, which kill more than 1.6 million patients each year worldwide, are difficult to treat due to the limited number of antifungal drugs (azoles, echinocandins, and polyenes) and the emergence of antifungal resistance. The transcription factor Crz1, a key regulator of cellular stress responses and virulence, is an attractive therapeutic target because this protein is absent in human cells. Here, we used a CRISPR-Cas9 approach to generate isogenic crz1Δ strains in two clinical isolates of caspofungin-resistant C. glabrata to analyze the role of this transcription factor in susceptibility to echinocandins, stress tolerance, biofilm formation, and pathogenicity in both non-vertebrate (Galleria mellonella) and vertebrate (mice) models of candidiasis. In these clinical isolates, CRZ1 disruption restores the susceptibility to echinocandins in both in vitro and in vivo models, and affects their oxidative stress response, biofilm formation, cell size, and pathogenicity. These results strongly suggest that Crz1 inhibitors may play an important role in the development of novel therapeutic agents against fungal infections considering the emergence of antifungal resistance and the low number of available antifungal drugs.

Original languageEnglish (US)
Article numbere0265777
JournalPLOS ONE
Volume17
Issue number3 March
DOIs
StatePublished - Mar 2022
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • General

Cite this