title: Antifungal activity of compounds targeting the Hsp90-calcineurin pathway against various mould species.
abstract: OBJECTIVE
  Invasive mould infections are associated with a high mortality rate and the emergence of MDR moulds is of particular concern. Calcineurin and its chaperone, the heat shock protein 90 (Hsp90), represent an important pathway for fungal virulence that can be targeted at different levels. We investigated the antifungal activity of compounds directly or indirectly targeting the Hsp90-calcineurin axis against different mould species.
  
  
  METHODS
  The in vitro antifungal activity of the anticalcineurin drug FK506 (tacrolimus), the Hsp90 inhibitor geldanamycin, the lysine deacetylase inhibitor trichostatin A and the Hsp70 inhibitor pifithrin-μ was assessed by the standard broth dilution method against 62 clinical isolates of Aspergillus spp. and non-Aspergillus moulds (Mucoromycotina, Fusarium spp., Scedosporium spp., Purpureocillium/Paecilomyces spp. and Scopulariopsis spp.)
  
  
  RESULTS
  FK506 had variable antifungal activity against different Aspergillus spp. and was particularly active against Mucor spp. Geldanamycin had moderate antifungal activity against Fusarium spp. and Paecilomyces variotii. Importantly, trichostatin A had good activity against the triazole-resistant Aspergillus ustus and the amphotericin B-resistant Aspergillus terreus as well as the MDR Scedosporium prolificans. Moreover, trichostatin A exhibited synergistic interactions with caspofungin against A. ustus and with geldanamycin against Rhizopus spp. for which none of the other agents showed activity. Pifithrin-μ exhibited little antifungal activity.
  
  
  CONCLUSIONS
  Targeting the Hsp90-calcineurin axis at different levels resulted in distinct patterns of susceptibility among different fungal species. Lysine deacetylase inhibition may represent a promising novel antifungal strategy against emerging resistant moulds.
authors.affiliation: Division of Infectious Diseases and International Health, Department of Medicine, Duke University Medical Center, Durham, NC, USA Clinical Microbiology Laboratory, Department of Pathology, Duke University Medical Center, Durham, NC, USA Service of Infectious Diseases, Department of Medicine, Lausanne University Hospital, Lausanne, Switzerland Institute of Microbiology, Lausanne University Hospital, Lausanne, Switzerland fredlamoth@gmail.com.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Lamoth
authors.affiliation: Division of Infectious Diseases and International Health, Department of Medicine, Duke University Medical Center, Durham, NC, USA Clinical Microbiology Laboratory, Department of Pathology, Duke University Medical Center, Durham, NC, USA.
authors.forename: Barbara D
authors.initials: BD
authors.lastname: Alexander
authors.affiliation: 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: Division of Pediatric Infectious Diseases, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA 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: D000935:Antifungal Agents / Q000494:pharmacology*; D019703:Calcineurin / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005658:Fungi / Q000187:drug effects* / Q000201:enzymology*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D008826:Microbial Sensitivity Tests
chemical_list: D000935:Antifungal Agents; D004791:Enzyme Inhibitors; D018841:HSP90 Heat-Shock Proteins; D019703:Calcineurin
keywords: geldanamycin; heat shock protein 70; heat shock protein 90; histone deacetylase inhibitors; pifithrin-μ; tacrolimus; trichostatin A