title: The fungicidal activity of amphotericin B requires autophagy-dependent targeting to the vacuole under a nutrient-starved condition in Saccharomyces cerevisiae.
abstract: In this study, we demonstrated that in distilled water, a nutrient-starved condition that elicits autophagy in Saccharomyces cerevisiae, an array of autophagy-deficient mutants are resistant to the fungicidal effects of amphotericin B. In addition, we found that a dansyl-labelled derivative of the antibiotic colocalized with disintegrated vacuoles throughout the cytoplasm in the amphotericin B-sensitive parental strain suspended in distilled water. In contrast, the dansyl-labelled derivative was not internalized in the Δatg18 strain, which is deficient in the formation of autophagosomes, a key early step in autophagy. However, the derivative accumulated without significant toxicity in structurally intact vacuoles in the Δvma1 mutant, which is deficient in the degradation of autophagic bodies, the final stage in autophagy. Our data support the idea that amphotericin B can utilize autophagy-dependent trafficking into the intra-vacuolar lumen, where it interacts with the luminal leaf of the membrane to cause structurally catastrophic effects.
authors.affiliation: Graduate School of Science, Osaka City University, 3-3-138 Sugimoto, Sumiyoshi-ku, Osaka 558-8585, Japan.
authors.forename: Michiru
authors.initials: M
authors.lastname: Yoshioka
authors.affiliation: Department of Chemistry and Chemical Biology, Gunma University, 1-5-1 Tenjin-cho, Kiryu, Gunma 376-8515, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Yamada
authors.affiliation: Graduate School of Science, Osaka City University, 3-3-138 Sugimoto, Sumiyoshi-ku, Osaka 558-8585, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Yamaguchi
authors.affiliation: Graduate School of Science, Osaka City University, 3-3-138 Sugimoto, Sumiyoshi-ku, Osaka 558-8585, Japan.|Research Center for Urban Health and Sports, Osaka City University, 3-3-138 Sugimoto, Sumiyoshi-ku, Osaka 558-8585, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Ogita
authors.affiliation: Graduate School of Science, Osaka City University, 3-3-138 Sugimoto, Sumiyoshi-ku, Osaka 558-8585, Japan.
authors.forename: Ken-Ichi
authors.initials: KI
authors.lastname: Fujita
authors.affiliation: Graduate School of Science, Osaka City University, 3-3-138 Sugimoto, Sumiyoshi-ku, Osaka 558-8585, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Tanaka
mesh_terms: D000666:Amphotericin B / Q000494:pharmacology*; D000935:Antifungal Agents / Q000494:pharmacology*; D000071182:Autophagosomes / Q000378:metabolism; D001343:Autophagy / Q000235:genetics* / Q000502:physiology; D000071183:Autophagy-Related Proteins / Q000235:genetics*; D025141:Drug Resistance, Fungal / Q000235:genetics*; D004875:Ergosterol / Q000378:metabolism; D017353:Gene Deletion; D008565:Membrane Proteins / Q000235:genetics*; D006180:Proton-Translocating ATPases / Q000235:genetics*; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics*
chemical_list: C441008:ATG18 protein, S cerevisiae; D000935:Antifungal Agents; D000071183:Autophagy-Related Proteins; D008565:Membrane Proteins; D029701:Saccharomyces cerevisiae Proteins; D000666:Amphotericin B; D006180:Proton-Translocating ATPases; C081687:VMA1 protein, S cerevisiae; D004875:Ergosterol