PubMed · 10201235
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A Ito. 1999. [Blastomycosis].. https://pubmed.ncbi.nlm.nih.gov/10201235/
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Clinical isolates of Candida auris show a high prevalence of resistance to Amphotericin B (AmB)-an uncommon trait in most Candida species. Alterations in ergosterol biosynthesis can contribute to acquired AmB resistance in C. auris laboratory strains but are rarely seen in clinical isolates. In this study, we experimentally evolved two drug-susceptible Clade II isolates of C. auris to develop AmB resistance. The evolved strains displayed a four to eight fold increase in MIC50 compared to the parental cells. We analyzed changes in their karyotype, genome, lipidome, and transcriptome associated with this acquired resistance. In one lineage, AOX2 was upregulated, and its deletion reversed the AmB resistance phenotype. The aox2Δ mutant also failed to evolve AmB resistance under experimental conditions. In the same lineage, restoring the UPC2 S332R and RTG3 S101T mutations to the wild-type allele restored AmB susceptibility. In another lineage, the ergosterol and sphingolipid pathways were observed to play a critical role, and upregulation of the ERG genes elevated the total sterol content, while significant downregulation of HSX11 (glucosylceramide synthase) resulted in lower levels of glucosylceramides. To our knowledge, this study is the first to show that AmB resistance in C. auris can be acquired through mechanisms both dependent on or independent of sterol content modulation, highlighting Aox2 and Upc2 as key regulators of amphotericin resistance.
Stearic acid esters of poly(ethylene oxide)-block-poly(hydroxyethyl L-aspartamide) and poly(ethylene oxide)-block-poly(hydroxyhexyl L-aspartamide) have been synthesized from poly(ethylene oxide)-block-poly(beta-benzyl L-aspartate) by polymer-analogous reactions and self-assembled into a micelle. Transmission electron microscopy and fluorescent probe studies reveal that the micelle mimics structural features of serum lipoproteins: it is nanoscopic, spherical, and has a supramolecular core-shell architecture, where the core is rich in fatty acid esters. As a result, the polymeric micelles effectively solubilize amphotericin B, a key drug for systemic mycoses. Serum lipoproteins solubilize many hydrophobic drugs as a biological transport system besides amphotericin B. A synthetic polymeric analogue may achieve the same aim, but with the ease of structural modification, safety, and stability.
In order to establish the physiological role of the Ca(2+)-activated Cl(-) current (I(Cl(Ca))) of chick primary afferent neurons, I measured the reversal potential of this current using either the amphotericin perforated patch technique (that alters intracellular Cl(-)) or the gramicidin perforated patch technique (that does not perturb intracellular Cl(-)). In the amphotericin experiments at 35 degrees C, I(Cl(Ca)) reversed at the Cl(-) equilibrium potential (E(Cl)=-24 mV) set by the superfusate (147 mM Cl(-)) and the pipette solution (60 mM Cl(-)). In contrast, in the gramicidin experiments at 35 degrees C, I(Cl(Ca)) reversed at -42+/-2 mV, midway between E(Cl) of the solutions and E(Cl) expected if Cl(-) were passively distributed. Thus the gramicidin perforated patch technique monitors Cl(-) currents without perturbing intracellular Cl(-). Further, the data imply that chick dorsal root ganglia (DRG) neurons actively accumulate Cl(-). I(Cl(Ca)) reversed at the same potential (-46+/-3 mV) at 20 degrees C indicating that the non-equilibrium distribution of Cl(-) is maintained at the lower temperature. Thus, I(Cl(Ca)) is a depolarizing current that can contribute to the after-depolarization in chick DRG neurons and thereby alter Ca(2+) influx.