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 dansyllabelled derivative was not internalized in the Datg18 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 Dvma1 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.

Lipid Systems for the Delivery of Amphotericin B in Antifungal Therapy

“…On the other hand, imaging of both normal epithelial and colon adenocarcinoma human cells exposed to AmB revealed a detoxifying mechanism based on the formation of AmB-containing exosomes devoid of cholesterol, suggesting that insertion of the drug within the hydrophobic membrane core is sufficient to disturb the membrane structure and lead to cytotoxic effects [61]. The fungicidal activity of AmB has also been attributed to vacuole disintegration resulting from trafficking of the drug to the vacuolar lumen via autophagy [70]. Moreover, oxidative cell damage to the lipid membrane that results from increased mitochondrial production and intracellular accumulation of reactive oxygen species (ROS) induced by AmB leads to impaired cellular functions and also contributes to the fungicidal activity of the drug [59,[63][64][65][66].…”

Efficacy and safety of amphotericin B formulations: a network meta-analysis and a multicriteria decision analysis

“…[1][2][3][4][5][6] Despite decades of clinical use, acquired resistance to AB is not frequent. [7][8][9][10] However, when conventionally formulated as AB deoxycholate, this treatment is responsible for many adverse events, including fever, nausea, vomiting, chills, rigours and two even more serious effects: anaemia and nephrotoxicity. [11][12][13] Renal impairment and nephrotoxicity are important events that can affect half of patients treated with AB.…”

Effect of nagilactone E on cell morphology and glucan biosynthesis in budding yeast Saccharomyces cerevisiae

“…AmB induces K + leakage from fungal cells via K + -specific pore formation because of direct interaction between AmB and ergosterol [34]. The conventionally used nonionic surfactant Triton X-100 induces leakage of 260 nm-absorbing materials including mainly nucleotides from cells due to non-specific disruption or solubilization of the plasma membrane phospholipids [22].…”