Miltefosine has post-antifungal effect and induces apoptosis in Cryptococcus yeasts.

Miltefosine has post-antifungal effect and induces apoptosis in Cryptococcus yeasts. Antimicrob Agents Chemother. 2018 May 29;: Authors: Spadari CC, Vila T, Rozental S, Ishida K Abstract Cryptococcus spp. are common opportunistic fungal pathogens, particularly in HIV patients. The approved drug miltefosine (MFS) has potential as an alternative antifungal against cryptococcosis; however, the mechanism of action of MFS in Cryptococcus is poorly understood. Here, we examined the effects of MFS on C. neoformans and C. gattii yeasts (planktonic and biofilm lifestyles), to clarify its mechanism of action. MFS presented inhibitory and fungicidal effects against planktonic Cryptococcus cells, with similar activity against dispersion biofilm cells, while sessile biofilm cells were less sensitive to MFS. Interestingly, MFS had post-antifungal effect on Cryptococcus, with a proliferation delay of up to 8.15 h after short exposure to fungicidal doses. MFS at fungicidal concentrations increased plasma membrane permeability, likely due to direct interaction with ergosterol, as suggested by competition assays with exogenous ergosterol. Moreover, MFS reduced the mitochondrial membrane potential, increased ROS production, and induced DNA fragmentation and condensation, all of which are hallmarks of apoptosis. Transmission electron microscopy analysis showed that MFS-treated yeasts had a reduced mucopolysaccharide capsule (confirmed by morphometry in ...
Source: Antimicrobial Agents and Chemotherapy - Category: Microbiology Authors: Tags: Antimicrob Agents Chemother Source Type: research