Selective Metal Chelation by a Thiosemicarbazone Derivative Interferes with Mitochondrial Respiration and Ribosome Biogenesis in Candida albicans

Abstract

The increasing incidence of fungal infections and resistance to existing antifungals call for the development of broad-spectrum antifungals with novel mechanisms of action. In this study, we demonstrate that a thiosemicarbazone derivative 19ak selectively inhibits mitochondrial respiration mainly by retarding mitochondrial respiratory chain complex I activity through iron chelation and inhibits ribosome biogenesis mainly by disrupting intracellular zinc homeostasis in C. albicans .

Combined Transcriptome and Metabolome Analysis Reveals That the Potent Antifungal Pyrylium Salt Inhibits Mitochondrial Complex I in Candida albicans

“…The mitochondria of C. albicans were isolated as previously described with some modifications ( 42 ). Briefly, C. albicans SC5314 cells were washed twice with PBS.…”

Hexyl-Aminolevulinate Ethosomes: a Novel Antibiofilm Agent Targeting Zinc Homeostasis in Candida albicans

“…Impairment of zinc utilization results in the inhibition of C. albicans protein translation ( 23 , 24 ), which explains the significant inhibition of biofilm growth and pathogenicity following HAL-ES-mediated treatment in our previous research ( 5 ). Approximately 8% of yeast proteins require zinc for their activity ( 25 ), especially enzymes related to pathogen survival and virulence as well as zinc finger transcription factors involved in transcriptional regulation ( 22 , 24 ).…”

“…Therefore, the uptake, storage, and utilization of zinc in C. albicans biofilms can be severely impaired by HAL-ES. A previous study found that simple zinc chelators only inhibited the growth of C. albicans , with concentrations well above the MIC required to produce a fungicidal effect ( 23 ). However, we found that the MIC and MFC were similar for HAL-ES because, compared to a zinc chelator, it caused an overall reduction in the uptake, storage, and utilization of zinc by C. albicans .…”

Study on the inhibitory activity and mechanism of Mentha haplocalyx essential oils nanoemulsion against Fusarium oxysporum growth

“…Ribosome biogenesis in eukaryotes is the basis of cell life and most cellular processes, including growth and cell division [51]. Some scholars have found that destroying the intracellular zinc homeostasis of C. albicans inhibits ribosome biogenesis in eukaryotes and then selectively inhibits mitochondrial respiration to prevent fungal contamination [52]. In eukaryotes, ribosome biogenesis involves producing and correctly assembling four rRNAs and approximately 80 ribosomal proteins [53].…”