title: Heat shock protein 90 (Hsp90): A novel antifungal target against Aspergillus fumigatus.
abstract: Invasive aspergillosis is a life-threatening and difficult to treat infection in immunosuppressed patients. The efficacy of current anti-Aspergillus therapies, targeting the cell wall or membrane, is limited by toxicity (polyenes), fungistatic activity and some level of basal resistance (echinocandins), or the emergence of acquired resistance (triazoles). The heat shock protein 90 (Hsp90) is a conserved molecular chaperone involved in the rapid development of antifungal resistance in the yeast Candida albicans. Few studies have addressed its role in filamentous fungi such as Aspergillus fumigatus, in which mechanisms of resistance may differ substantially. Hsp90 is at the center of a complex network involving calcineurin, lysine deacetylases (KDAC) and other client proteins, which orchestrate compensatory repair mechanisms of the cell wall in response to the stress induced by antifungals. In A. fumigatus, Hsp90 is a trigger for resistance to high concentrations of caspofungin, known as the paradoxical effect. Disrupting Hsp90 circuitry by different means (Hsp90 inhibitors, KDAC inhibitors and anti-calcineurin drugs) potentiates the antifungal activity of caspofungin, thus representing a promising novel antifungal approach. This review will discuss the specific features of A. fumigatus Hsp90 and the potential for antifungal strategies of invasive aspergillosis targeting this essential chaperone.
authors.affiliation: a Division of Pediatric Infectious Diseases, Department of Pediatrics , Duke University Medical Center , Durham , NC , USA .|b Infectious Diseases Service, Department of Medicine , Lausanne University Hospital , Lausanne , Switzerland .|c Institute of Microbiology, Lausanne University Hospital , Lausanne , Switzerland , and.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Lamoth
authors.affiliation: a Division of Pediatric Infectious Diseases, Department of Pediatrics , Duke University Medical Center , Durham , NC , USA .
authors.forename: Praveen R
authors.initials: PR
authors.lastname: Juvvadi
authors.affiliation: a Division of Pediatric Infectious Diseases, Department of Pediatrics , Duke University Medical Center , Durham , NC , USA .|d Department of Molecular Genetics and Microbiology , Duke University Medical Center , Durham , NC , USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Steinbach
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001228:Aspergillosis / Q000188:drug therapy / Q000382:microbiology*; D001232:Aspergillus fumigatus / Q000187:drug effects* / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D025141:Drug Resistance, Fungal; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D050296:Microbial Viability / Q000187:drug effects; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D013312:Stress, Physiological
chemical_list: D000935:Antifungal Agents; D002352:Carrier Proteins; D018841:HSP90 Heat-Shock Proteins
keywords: Antifungal resistance; Aspergillus fumigatus; calcineurin; geldanamycin; heat shock protein 90; invasive aspergillosis; lysine deacetylase; trichostatinA