Unraveling Caspofungin Resistance in Cryptococcus neoformans

Abstract

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.

Red-shifted and pH-responsive imidazole-based azo dyes with potent antimicrobial activity

“…C. neoformans is responsible for a high mortality rate among infected individuals and drug resistance is an actual problem. 30 Although filamentous fungi such as Aspergillus spp.…”

“…C. neoformans is responsible for a high mortality rate among infected individuals and drug resistance is an actual problem. 30 Although filamentous fungi such as Aspergillus spp. were not very sensitive to the compounds, their activity against the dermatophytes tested (particularly Trichophyton rubrum and T. mentagrophytes , frequently involved in superficial mycoses 31 ) was moderate, with the MIC from 64 to 16 μg mL −1 .…”

Arginine methylation of Puf4 drives diverse protein functions

“…Samples were quantified using the second-derivative maximum method and fitted to a standard curve of five 4-fold serial dilutions of cDNA. Primer sequences were previously published 28 .…”

“…Puf4 regulates mRNAs involved in cell wall biosynthesis and is involved in the splicing of HXL1, the major endoplasmic reticulum (ER) stress transcription factor 26,27 . Of note, puf4D mutants are resistant to the ER stress-inducing drug tunicamycin and the antifungal drug caspofungin [26][27][28] .…”

Nanotechnology-Based Approaches for Voriconazole Delivery Applied to Invasive Fungal Infections

“…In addition, Cryptococcus sp. has intrinsic resistance to echinocandins [ 126 ]. In this sense, the treatment of cryptococcosis is a challenge, and the search for new alternatives has grown in recent years [ 127 ], such as the combination of antifungal drugs [ 128 ], the use of nanotechnology, and the search for new molecular targets [ 129 , 130 , 131 ].…”