PubMed · 5223309
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M Mage. 1966. Moniliasis.. https://pubmed.ncbi.nlm.nih.gov/5223309/
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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.
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Intravenously injectable o/w emulsions of drugs being poorly soluble in water and simultaneously in oils need to be produced by locating the drug in the interfacial lecithin layer, e.g. amphotericin B. For achieving this, up to now organic solvents were required. The objective was to develop a solvent-free production method for such emulsions. Drug and the pre-formed parenteral emulsion Lipofundin were mixed and subjected to high pressure homogenisation. Drug powder and emulsions were characterised regarding size and physical stability by photon correlation spectroscopy (PCS), laser diffractometry (LD) and zeta potential measurements. Drug incorporation was studied using light microscopy, electron microscopy (EM) and a centrifugation test to separate non-dissolved drug. Amphotericin B and carbamazepine were used as model drugs. The high streaming velocities lead to accelerated drug dissolution and partitioning into the interfacial layer (so-called "solubilisation by emulsification", SolEmuls Technology). The interfacial layer could incorporate (solubilise) a certain amount of drug, revealed by EM pictures. Exceeding this concentration, hybrid dispersions were formed consisting of drug-loaded oil droplets and drug nanocrystals of similar size (approximately 200 nm). Both dispersion types are i.v. injectable opening the opportunity to deliver the drug in a concentrated form at desired low injection volume, e.g. 10 mg/ml.