Caspofungin Affects Extracellular Vesicle Production and Cargo in Candida auris

Abstract

Antifungal resistance has become more frequent, either due to the emergence of naturally resistant species or the development of mechanisms that lead to resistance in previously susceptible species. Among these fungal species of global threat, Candida auris stands out for commonly being highly resistant to antifungal drugs, and some isolates are pan-resistant. The rate of mortality linked to C. auris infections varies from 28% to 78%. In this study, we characterized C. auris extracellular vesicles (EVs) in the presence of caspofungin, an echinocandin, which is the recommended first line antifungal for the treatment of infections due to this emerging pathogen. Furthermore, we also analyzed the protein and RNA content of EVs generated by C. auris cultivated with or without treatment with caspofungin. We observed that caspofungin led to the increased production of EVs, and treatment also altered the type and quantity of RNA molecules and proteins enclosed in the EVs. There were distinct classes of RNAs in the EVs with ncRNAs being the most identified molecules, and tRNA-fragments (tRFs) were abundant in each of the strains studied. We also identified anti-sense RNAs, varying from 21 to 55 nt in length. The differentially abundant mRNAs detected in EVs isolated from yeast subjected to caspofungin treatment were related to translation, nucleosome core and cell wall. The differentially regulated proteins identified in the EVs produced during caspofungin treatment were consistent with the results observed with the RNAs, with the enriched terms being related to translation and cell wall. Our study adds new information on how an echinocandin can affect the EV pathway, which is associated with the yeast cell being able to evade treatment and persist in the host. The ability of C. auris to efficiently alter the composition of EVs may represent a mechanism for the fungus to mitigate the effects of antifungal agents.

Liposomal formulation of a new antifungal hybrid compound provides protection against Candida auris in the ex vivo skin colonization model

“…Firstly, the size of the produced vesicles increased, even by 22 nm for the B11785 strain. This observation is consistent with the results obtained for caspofungin, where also an increase of the size of EVs upon drug treatment was recorded ( 50 ). Secondly, their concentration decreased significantly at the same time, especially in the case of the B11203 and B11799 strains.…”

“…Secondly, their concentration decreased significantly at the same time, especially in the case of the B11203 and B11799 strains. This is a different phenomenon compared with the response observed to caspofungin treatment, where an increased amount of EVs was observed ( 50 ). On this basis, it can be concluded that PQA-Az-13 induced the production of a smaller number of EVs than in the case of the control, but at the same time, they were at least 10% larger by size.…”

TheCryptococcusextracellular vesicle transcriptome

“…We also know that the growth conditions can have a strong influence on EV production and EV composition in fungi (Reis et al . 2021; Amatuzzi et al . 2022; Rizzo et al .…”

Microbial extracellular vesicles contribute to antimicrobial resistance

“…A study has shown that when Candida auris is treated with caspofungin, the EV production significantly increases. At the same time, this treatment changed the protein composition within EVs, including proteins associated with the cell wall [ 70 ]. In addition, Zhao and colleagues [ 71 ] found that saccharomyces cerevisiae with defects in cell wall synthesis release a large amount of EVs rich in cell wall-synthesizing enzymes, such as glucan synthase subunits Fks1 and chitin synthase Chs3.…”