title: In vitro and in vivo role of heat shock protein 90 in Amphotericin B resistance of Aspergillus terreus.
abstract: Aspergillus terreus (A. terreus) is of serious concern because of a high propensity to dissemination and in vitro and in vivo resistance to Amphotericin B (AmB). The underlying molecular mechanism of AmB is not known yet and here we want to explore whether fungal heat shock protein 90 (HSP90) is involved in polyene resistance in A. terreus. AmB-susceptible (ATS) and AmB-resistant (ATR) A. terreus and AmB-susceptible Aspergillus fumigatus (AFS) were investigated in response to AmB with a special focus on HSP90. HSP90 inhibitors resulted in significant improvement of AmB activity against ATR as minimum inhibitory concentrations (MIC) decreased from 32 to 0.38 mg/L. Gene expression profiling showed a greater basal amount of HSP90 levels in ATR and ATS when compared with AFS. HSP90 blockers in combination with AmB were evaluated in a murine model of disseminated aspergillosis. HSP90 inhibitors were not beneficial for mice infected with ATR, and neither mono- nor combination treatment with AmB yielded clinical improvement. HSP90 inhibition with 17-allylamino-17-demethoxygeldanamycin (17-AAG) was harmful. HSP90 seems to play a vital role in antifungal stress response in all aspergilli tested, whereas HSP90 does not substantiate the origin of AmB resistance in ATR.
authors.affiliation: Division of Hygiene and Medical Microbiology, Innsbruck Medical University. Electronic address: cornelia.lass-floerl@i-med.ac.at.
authors.forename: G
authors.initials: G
authors.lastname: Blum
authors.affiliation: Division of Hygiene and Medical Microbiology, Innsbruck Medical University.
authors.forename: B
authors.initials: B
authors.lastname: Kainzner
authors.affiliation: Division of Hygiene and Medical Microbiology, Innsbruck Medical University.
authors.forename: K
authors.initials: K
authors.lastname: Grif
authors.affiliation: Innsbruck Central Animal Experiment Station.
authors.forename: H
authors.initials: H
authors.lastname: Dietrich
authors.affiliation: Department of Pathology, Innsbruck Medical University.
authors.forename: B
authors.initials: B
authors.lastname: Zeiger
authors.affiliation: Department of Internal Medicine I, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: T
authors.initials: T
authors.lastname: Sonnweber
authors.affiliation: Division of Hygiene and Medical Microbiology, Innsbruck Medical University.
authors.forename: C
authors.initials: C
authors.lastname: Lass-Flörl
mesh_terms: D000666:Amphotericin B / Q000494:pharmacology*; D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology; D001230:Aspergillus / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D015169:Colony Count, Microbial; D025141:Drug Resistance, Fungal; D005260:Female; D005656:Fungal Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D053208:Kaplan-Meier Estimate; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D000935:Antifungal Agents; D005656:Fungal Proteins; D018841:HSP90 Heat-Shock Proteins; D000666:Amphotericin B