title: Blocking Hsp70 enhances the efficiency of amphotericin B treatment against resistant Aspergillus terreus strains.
abstract: The polyene antifungal amphotericin B (AmB) is widely used to treat life-threatening fungal infections. Even though AmB resistance is exceptionally rare in fungi, most Aspergillus terreus isolates exhibit an intrinsic resistance against the drug in vivo and in vitro. Heat shock proteins perform a fundamental protective role against a multitude of stress responses, thereby maintaining protein homeostasis in the organism. In this study, we elucidated the role of heat shock protein 70 (Hsp70) family members and compared resistant and susceptible A. terreus clinical isolates. The upregulation of cytoplasmic Hsp70 members at the transcriptional as well as translational levels was significantly higher with AmB treatment than without AmB treatment, particularly in resistant A. terreus isolates, thereby indicating a role of Hsp70 proteins in the AmB response. We found that Hsp70 inhibitors considerably increased the susceptibility of resistant A. terreus isolates to AmB but exerted little impact on susceptible isolates. Also, in in vivo experiments, using the Galleria mellonella infection model, cotreatment of resistant A. terreus strains with AmB and the Hsp70 inhibitor pifithrin-μ resulted in significantly improved survival compared with that achieved with AmB alone. Our results point to an important mechanism of regulation of AmB resistance by Hsp70 family members in A. terreus and suggest novel drug targets for the treatment of infections caused by resistant fungal isolates.
authors: Division of Hygiene and Medical Microbiology, Medical University of Innsbruck, Innsbruck, Austria.
authors: Michael
authors: M
authors: Blatzer
authors: Division of Hygiene and Medical Microbiology, Medical University of Innsbruck, Innsbruck, Austria.
authors: Gerhard
authors: G
authors: Blum
authors: Division of Hygiene and Medical Microbiology, Medical University of Innsbruck, Innsbruck, Austria.
authors: Emina
authors: E
authors: Jukic
authors: Division of Hygiene and Medical Microbiology, Medical University of Innsbruck, Innsbruck, Austria.
authors: Wilfried
authors: W
authors: Posch
authors: Division of Medical Biochemistry, Medical University of Innsbruck, Innsbruck, Austria.
authors: Peter
authors: P
authors: Gruber
authors: Division of Hygiene and Medical Microbiology, Medical University of Innsbruck, Innsbruck, Austria.
authors: Markus
authors: M
authors: Nagl
authors: Division of Hygiene and Medical Microbiology, Medical University of Innsbruck, Innsbruck, Austria.
authors: Ulrike
authors: U
authors: Binder
authors: Division of Hygiene and Medical Microbiology, Medical University of Innsbruck, Innsbruck, Austria.
authors: Elisabeth
authors: E
authors: Maurer
authors: Biocenter, Division of Clinical Biochemistry, Medical University of Innsbruck, Innsbruck, Austria.
authors: Bettina
authors: B
authors: Sarg
authors: Biocenter, Division of Clinical Biochemistry, Medical University of Innsbruck, Innsbruck, Austria.
authors: Herbert
authors: H
authors: Lindner
authors: Division of Hygiene and Medical Microbiology, Medical University of Innsbruck, Innsbruck, Austria.
authors: Cornelia
authors: C
authors: Lass-Flörl
authors: Division of Hygiene and Medical Microbiology, Medical University of Innsbruck, Innsbruck, Austria doris.wilflingseder@i-med.ac.at.
authors: Doris
authors: D
authors: Wilflingseder
mesh_terms: D000666:Amphotericin B / Q000494:pharmacology*; D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D001228:Aspergillosis / Q000188:drug therapy; D001230:Aspergillus / Q000187:drug effects*; D025141:Drug Resistance, Fungal / Q000187:drug effects; D004359:Drug Therapy, Combination; D018840:HSP70 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D008826:Microbial Sensitivity Tests; D009036:Moths / Q000382:microbiology; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: C545747:2-phenylacetylenesulfonamide; D000935:Antifungal Agents; D018840:HSP70 Heat-Shock Proteins; D013449:Sulfonamides; D000666:Amphotericin B