PubMed · 5427858
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R McDonald, E N Greenberg, R Kramer. 1970. Cryptococcal meningitis.. https://doi.org/10.1136/adc.45.241.417
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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.
Amphotericin B is an antimycotic agent that has been studied for a long time, both because of its pharmacological action and the interest in understanding how this ionic channel works. It has been proposed that the channel is formed by a barrel of monomers, and that the presence of sterol is needed for the formation of such a barrel. As a matter of fact this need of a sterol has been used as a guiding idea in attempts to design derivatives more efficient in the discrimination of the cholesterol containing membranes, as compared to the ergosterol containing ones, henceforth diminishing the unwanted side effects in its pharmacological use. In this work we show that unitary channels that appear in a cholesterol containing membrane also appear when this membrane is free of cholesterol. We prove this to be the case for two membranes, a biological one, asolectin, and a synthetic one, DMPC. We then advance the idea that the role of sterols in the formation of the amphotericin B channel is related to the effects they have on the structure of the membrane itself, rather than to a direct involvement in the channel formation. We further look into the effect that different cholesterol concentrations in the membrane produce on the single channel properties.
Using the monolayer technique to study the surface behaviour of systems consisting of amphotericin B (AmB) and various sterols, the components were found to interact with each other. The interactions observed are accounted for by postulating that, at low surface pressures, AmB and different sterols form mixed films where the former lies parallel and the latter normal to the air-water interface in such a way that the polar groups in both components establish hydrogen bonds that lead to the formation of an AmB-sterol 'complex' of 2:1 stoichiometry at the interface. At high surface pressures, AmB molecules rearrange themselves normal to the interface; this gives rise to the Van der Waals interactions between non-polar chains of both components that vary with the nature and composition of the system. The occurrence of these hydrophobic interactions prevents the desorption of AmB into the subphase, which is consistent with the positive excess areas of mixing obtained under these surface pressure conditions. Among the four sterols studied, ergosterol exhibits the strongest interaction with AmB and beta-sitosterol the weakest. Cholesterol and stigmasterol show intermediate behaviour.