Unraveling Caspofungin Resistance in Cryptococcus neoformans

Cryptococcus neoformans is a basidiomycetous yeast responsible for hundreds of thousands of deaths a year and is particularly threatening in immunocompromised patients. There are few families of antifungals that are available to fight fungal infections, and the unique efficient treatment for the most deadly cerebral forms of cryptococcosis is based on a combination of 5-fluorocytosine and amphotericin B. The toxicities of both compounds are elevated, and more therapeutic options are urgently needed for better management of life-threatening cryptococcosis. The newest class of antifungals, i.e., echinocandins, has initially led to great hope. Unfortunately, C. neoformans was rapidly confirmed to be naturally resistant to these molecules, notably caspofungin. In this respect, we discuss here the recent key findings of the Panepinto research group published in mBio (M. C. Kalem et al., mBio 12:e03225-20, 2021, https://doi:10.1128/mBio.03225-20) that provide an unprecedented view of how C. neoformans regulates caspofungin resistance through a complex posttranscriptional regulation of cell wall biosynthesis genes.