Fungicidal activity and morphological alterations of Candida albicans induced by echinocandins: study of strains with reduced caspofungin susceptibility

Abstract

Caspofungin is a member of the echinocandin class of antifungal compounds that inhibit 1,3-β-d-Glucan synthase. As patient exposure to caspofungin (CAS) broadens, the number of infecting strains with reduced susceptibility to this drug is expected to rise. In the present study, the in vitro effects of varying concentrations of CAS against Candida albicans isolates presenting reduced susceptibility to CAS were studied in comparison with a reference strain. Two C. albicans isolates presenting high minimal inhibitory concentrations (MIC = 8 μg ml(-1) ) were selected: one isolate obtained in the laboratory under continuous antifungal selection pressure (CaIn-R) and one clinical isolate (CaClin-R) from a patient with a therapeutic failure. Results showed that after 24 h of CAS exposure, CaIn-R and CaClin-R presented a partial growth inhibition in comparison with the reference strain. Moreover, scanning electron microscopy and transmission electron microscopy studies showed that the cell walls of CaIn-R and CaClin-R were less altered than that of the reference strain. These observations suggested that although CaIn-R and CaClin-R cells were misshapen after CAS exposure, cell lysis was limited after 24 h of treatment indicating higher survival ability for CaIn-R and CaClin-R in the presence of CAS.

Nanoscale analysis of caspofungin-induced cell surface remodelling in Candida albicans

“…30 Moreover, substantial alteration of the C. albicans cell surface structure was clearly observed, the surface roughness (calculated on 500 nm × 500 nm height images) increasing from ~1 nm, for untreated cells, to ~5 nm, for treated cells. These AFM observations are qualitatively consistent with electron microscopy investigations 22 showing progressive disintegration of the cell wall after exposure to caspofungin. We note that similar morphological and structural changes were observed in the yeasts C. glabrata and S. cerevisiae (Supplementary Fig.…”

“…2b) revealed a smooth and homogeneous surface, consistent with the presence of an outer layer of mannoproteins and with earlier electron microscopy data. 21,22 …”

Characterization of a Distinct Host Response Profile to Pneumocystismurina Asci during Clearance of Pneumocystis Pneumonia

“…In the case of P. murina, reduction in de novo synthesis of ␤-glucan by inhibition of ␤-1,3-glucan synthase with anidulafungin treatment appears to cause lysis of existing asci, in addition to preventing development of new asci (7). The effects of anidulafungin treatment on P. murina asci appear to be similar to the fungicidal effects of caspofungin treatment on Candida albicans that lead to killing of actively growing cells by inducing changes in the cell wall that cause osmotic instability and eventual cell lysis (48). The lack of activity of anidulafungin treatment against P. murina trophic forms supports previous findings that this form of the organism does not contain ␤-glucan.…”

Antifungal coatings by caspofungin immobilization onto biomaterials surfaces via a plasma polymer interlayer

“…It should be noted that there has been discussion of other mechanisms by which caspofungin may act, including altering the cell morphology, [26][27][28] lowering the cell wall mechanical strength, and increasing the sensitivity to osmotic pressure, which could eventually lead to cell lysis and death. 29,30 Studying the relevance of these postulated mechanisms in the context of surface-bound echinocandins would need to be established through further experimentation.…”