title: New insight into amphotericin B resistance in Aspergillus terreus.
abstract: Amphotericin B (AMB) is the predominant antifungal drug, but the mechanism of resistance is not well understood. We compared the in vivo virulence of an AMB-resistant Aspergillus terreus (ATR) isolate with that of an AMB-susceptible A. terreus isolate (ATS) using a murine model for disseminated aspergillosis. Furthermore, we analyzed the molecular basis of intrinsic AMB resistance in vitro by comparing the ergosterol content, cell-associated AMB levels, AMB-induced intracellular efflux, and prooxidant effects between ATR and ATS. Infection of immunosuppressed mice with ATS or ATR showed that the ATS strain was more lethal than the ATR strain. However, AMB treatment improved the outcome in ATS-infected mice while having no positive effect on the animals infected with ATR. The in vitro data demonstrated that ergosterol content is not the molecular basis for AMB resistance. ATR absorbed less AMB, discharged more intracellular compounds, and had better protection against oxidative damage than the susceptible strain. Our experiments showed that ergosterol content plays a minor role in intrinsic AMB resistance and is not directly associated with intracellular cell-associated AMB content. AMB might exert its antifungal activity by oxidative injury rather than by an increase in membrane permeation.
authors: Department of Hygiene and Social Medicine, Innsbruck Medical University, Innsbruck, Austria. gerhard.blum@i-med.ac.at
authors: Gerhard
authors: G
authors: Blum
authors: Caroline
authors: C
authors: Hörtnagl
authors: Emina
authors: E
authors: Jukic
authors: Thomas
authors: T
authors: Erbeznik
authors: Thomas
authors: T
authors: Pümpel
authors: Hermann
authors: H
authors: Dietrich
authors: Markus
authors: M
authors: Nagl
authors: Cornelia
authors: C
authors: Speth
authors: Günter
authors: G
authors: Rambach
authors: Cornelia
authors: C
authors: Lass-Flörl
mesh_terms: D000666:Amphotericin B / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001228:Aspergillosis / Q000188:drug therapy*; D001230:Aspergillus / Q000187:drug effects / Q000378:metabolism / Q000472:pathogenicity*; D025141:Drug Resistance, Fungal / Q000235:genetics / Q000502:physiology*; D015227:Lipid Peroxidation / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests
chemical_list: D000935:Antifungal Agents; D000666:Amphotericin B