Micafungin triggers caspase-dependent apoptosis inCandida albicansandCandida parapsilosisbiofilms, including caspofungin non-susceptible isolates

Abstract

Candida biofilms play an important role in infections associated with medical devices and are resistant to antifungals. We hypothesized that the echinocandin micafungin (MICA) exerts an enhanced antifungal activity against caspofungin (CAS)-susceptible (CAS-S) and CAS-non-susceptible (CAS-NS) Candida albicans and Candida parapsilosis which is at least in part through apoptosis, even in the biofilm environment. Apoptosis was characterized by detecting reactive oxygen species (ROS) accumulation, depolarization of mitochondrial membrane potential (MMP), DNA fragmentation, lack of plasma membrane integrity, and metacaspase activation following exposure of Candida biofilm to MICA for 3h at 37 C in RPMI 1640 medium. The minimum inhibitory concentration was higher for CAS (2.0-16.0 mg/ mL) than for MICA (1.0-8.0 mg/mL) for Candida biofilms. Elevated intracellular ROS levels and depolarization of MMP was evident in CAS-S C. albicans (3.0-4.2 fold) and C. parapsilosis (4.8-5.4 fold) biofilms compared with CAS-NS (1.2 fold) after exposure to MICA (0.25x-1xMIC). Elevated intracellular ROS levels and depolarization of MMP was evident in CAS-S C. albicans (3.0-4.2 fold) and C. parapsilosis (4.8-5.4 fold) biofilms compared with CAS-NS (1.2 fold) after exposure to MICA (0.25x-1xMIC). Finally higher ß-1, 3 glucan levels were seen in sessile cells compared to planktonic cells, especially in CAS-NS strains. MICA treatment might induce a metacaspase-dependent apoptotic process in biofilms of both CAS-S C. albicans and C. parapsilosis, and to some degree in CAS-NS strains.

Synergistic effect of nikkomycin Z with caspofungin and micafungin against Candida albicans and Candida parapsilosis biofilms

“…Interestingly, micafungin showed higher synergism combined with nikkomycin Z both against C. albicans and C. parapsilosis biofilms compared to the combination of caspofungin and nikkomycin Z. This striking synergy observed can be explained by micafungin-induced extended production of reactive oxygen species and increased apoptosis as reported by Shirazi and Kontoyiannis (2015). Our study was subject to two limitations.…”

Activity of exogenous tyrosol in combination with caspofungin and micafungin against Candida parapsilosis sessile cells

“…). Furthermore, enhanced micafungin activity was observed against C. parapsilosis biofilm earlier by Shirazi and Kontoyiannis (). On the other hand, Quindós et al .…”

Difficult but Not Impossible: in Search of an Anti-Candida Vaccine

“…The molecule used against them is mannose-binding lectin (MBL), a protein that is synthesized in the liver and involved in complement cascade activation. Investigations of its function have found MBL-induced agglutination in the yeast Recombinant heat shock proteins: r-hsp90-CA [9,11] Laminarin: CRM197 [12] Replicative aging [23][24][25] Respiratory pathways: Mir1 [26] Sphingolipid metabolism: BHBM, D13 [27] Micafungin activated metacaspase complexes [28] Tricyclic antidepressants [16] Genetically engineered organisms: Lactobacillus casei containing the Eno1p antigen [29] phase to treat both C. glabrata and C. albicans. This was achieved through binding to the mannoproteins covering the fungal cell surface, inducing complement activation [15•].…”

“…The delivery method of this vaccine would require evasion of host immune response, likely by encasement in a lipid endosome. In a study involving micafungin-activated metacaspase complexes, the antifungal increased reactive oxygen species, lowered mitochondrial membrane potential, and activated metacaspase activity in caspofungin susceptible and non-susceptible C. albicans and C. parapsilosis [28]. The major drawback to this therapy is that micafungin is a foreign molecule, and thus the fungal cell may recognize this and develop resistance mechanisms, such as efflux pumps or inactivating enzymes.…”