Cellular apoptosis and necrosis as therapeutic targets for novel Eugenol Tosylate Congeners against Candida albicans

Abstract

Despite the rise of new Candida species, Candida albicans tops the list with high morbidity and mortality rates. to tackle this problem there is a need to explore new antifungals that could replace or augment the current treatment options. We previously reported that tosylation of eugenol on hydroxyl group resulted in molecules with enhanced antifungal potency. in line with that work, we synthesized new eugenol tosylate congeners (ETC-1-ETC-7) with different substituents on pendent sulfonyl group and tested their susceptibility against different fluconazole susceptible and resistant C. albicans strains. We evaluated physiology and mode of cell death in response to the most active derivatives by analyzing major apoptotic markers in yeast such as phosphatidylserine externalization, DnA fragmentation, mitochondrial depolarization and decrease in cytochrome c oxidase activity. the results demonstrated that all C. albicans strains were variably susceptible to the test compounds with Mic ranging from 0.125-512 µg/ml, and the most active compounds (ETC-5, ETC-6 and ETC-7) actuate apoptosis and necrosis in Candida cells in a dose-dependent manner via metacaspase-dependent pathway. Furthermore haemolytic assay showed low cytotoxicity effect of these ETCs. Overall the results indicated that etcs exhibit potential antifungal activity against C. albicans by activating apoptotic and necrotic pathways.

Piperidine based 1,2,3-triazolylacetamide derivatives induce cell cycle arrest and apoptotic cell death in Candida auris

“…Further, TUNNEL assay corroborates the apoptotic nature of these three compounds against C. auris cells and the observations are in accord with previous literature, where researchers have documented dose dependent effect of natural compounds on induction of apoptosis and DNA damage in Candida cells [41] , [42] . These findings are also in agreement with our research findings where semi-synthetic compounds were reported to cause dose dependent late apoptosis in C. albicans [5] , [21] .…”

“…For studying apoptotic markers, protoplasts of C. auris MRL6057 were prepared as explained previously [21] . Briefly, cells grown for 8 h were then exposed for 4 h to ¼ MIC, ½ MIC and MIC of test compounds.…”

“…The test compounds were evaluated for their cytotoxic activity using horse red blood cells (NHLS, South Africa). The compounds were evaluated for their cytotoxic nature by method explained previously [21] , with modifications. Briefly, 10 mL horse blood was aliquoted in 50 mL sterile falcon tubes, spinning for 10 min at 2000 rpm.…”

Phytogenic Fabrication of Ag–Fe Bimetallic Nanoparticles for Cell Cycle Arrest and Apoptosis Signaling Pathways in Candida auris by Generating Oxidative Stress

“…Antifungal susceptibility testing for Ag–Fe NPs was performed by broth microdilution assay against 25 clinical strains of C. auris , following the Clinical and Laboratory Standards Institute guidelines [ 51 ]. The concentration ranges of Ag–Fe NPs and amphotericin B (positive control) used were 12.5–0.02 µg/mL and 16–0.031 µg/mL, respectively.…”

Enhanced Efficacy of Thiosemicarbazone Derivative-Encapsulated Fibrin Liposomes against Candidiasis in Murine Model

“…The compound showed a better activity than the reference drug itraconazole for the Candida strain, and this best activity was observed due to the presence of the p -chlorophenyl group [ 28 ]. Recent studies have indicated the presence of apoptosis in yeast induced by different agents [ 58 , 59 ]. Dying C. albicans cells have been reported to exhibit chromatin condensation, nuclear fragmentation, and DNA damage—the key markers of apoptosis [ 60 , 61 ].…”