Miltefosine Has a Postantifungal Effect and Induces Apoptosis in Cryptococcus Yeasts

Antimicrobial Agents and Chemotherapy
Cristina C SpadariKelly Ishida

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 activities against dispersion biofilm cells, while sessile biofilm cells were less sensitive to MFS. Interestingly, MFS had postantifungal effect on Cryptococcus, with a proliferation delay of up to 8.15 h after a short exposure to fungicidal doses. MFS at fungicidal concentrations increased the plasma membrane permeability, likely due to a direct interaction with ergosterol, as suggested by competition assays with exogenous ergosterol. Moreover, MFS reduced the mitochondrial membrane potential, increased reactive oxygen species (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...Continue Reading

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Citations

Aug 21, 2020·Antimicrobial Agents and Chemotherapy·Yongqin WuSean X Zhang
Nov 19, 2020·Antibiotics·Jong H KimKirkwood M Land
Nov 14, 2020·Genes·Mónica GalochaMiguel Cacho Teixeira
Aug 10, 2021·Frontiers in Cellular and Infection Microbiology·Rodrigo Rollin-PinheiroEliana Barreto-Bergter

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