title: T-2307 causes collapse of mitochondrial membrane potential in yeast.
abstract: T-2307, an arylamidine compound, has been previously reported to have broad-spectrum in vitro and in vivo antifungal activities against clinically significant pathogens, including Candida species, Cryptococcus neoformans, and Aspergillus species, and is now undergoing clinical trials. Here we investigated the mechanism of action of T-2307 using yeast cells and mitochondria isolated from yeast and rat liver. Nonfermentative growth of Candida albicans and Saccharomyces cerevisiae in glycerol medium, in which yeasts relied on mitochondrial respiratory function, was inhibited at 0.001 to 0.002 μg/ml (0.002 to 0.004 μM) of T-2307. However, fermentative growth in dextrose medium was not inhibited by T-2307. Microscopic examination using Mitotracker fluorescent dye, a cell-permeant mitochondrion-specific probe, demonstrated that T-2307 impaired the mitochondrial function of C. albicans and S. cerevisiae at concentrations near the MIC in glycerol medium. T-2307 collapsed the mitochondrial membrane potential in mitochondria isolated from S. cerevisiae at 20 μM. On the other hand, in isolated rat liver mitochondria, T-2307 did not have any effect on the mitochondrial membrane potential at 10 mM. Moreover, T-2307 had little inhibitory and stimulatory effect on mitochondrial respiration in rat liver mitochondria. In conclusion, T-2307 selectively disrupted yeast mitochondrial function, and it was also demonstrated that the fungal mitochondrion is an attractive antifungal target.
authors.affiliation: Research Laboratories, Toyama Chemical Co., Ltd., Toyama, Japan. tatsuya_shibata@toyama-chemical.co.jp
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Shibata
authors.forename: Toshinari
authors.initials: T
authors.lastname: Takahashi
authors.forename: Eio
authors.initials: E
authors.lastname: Yamada
authors.forename: Akiko
authors.initials: A
authors.lastname: Kimura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nishikawa
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Hayakawa
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Nomura
authors.forename: Junichi
authors.initials: J
authors.lastname: Mitsuyama
mesh_terms: D000818:Animals; D002176:Candida albicans / Q000187:drug effects* / Q000378:metabolism; D005285:Fermentation; D005456:Fluorescent Dyes; D005947:Glucose / Q000378:metabolism; D005990:Glycerol / Q000378:metabolism; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D009930:Organic Chemicals; D010085:Oxidative Phosphorylation / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000378:metabolism; D013045:Species Specificity
chemical_list: D005456:Fluorescent Dyes; D009930:Organic Chemicals; C107472:red dye CMXRos; D005947:Glucose; D005990:Glycerol