title: Identification and characterization of haemofungin, a novel antifungal compound that inhibits the final step of haem biosynthesis.
abstract: OBJECTIVE
  During recent decades, the number of invasive fungal infections among immunosuppressed patients has increased significantly, whereas the number of effective systemic antifungal drugs remains low and unsatisfactory. The aim of this study was to characterize a novel antifungal compound, CW-8/haemofungin, which we previously identified in a screen for compounds affecting fungal cell wall integrity.
  
  
  METHODS
  The in vitro characteristics of haemofungin were investigated by MIC evaluation against a panel of pathogenic and non-pathogenic fungi, bacteria and mammalian cells in culture. Haemofungin mode-of-action studies were performed by screening an Aspergillus nidulans overexpression genomic library for resistance-conferring plasmids and biochemical validation of the target. In vivo efficacy was tested in the Galleria mellonella and Drosophila melanogaster insect models of infection.
  
  
  RESULTS
  We demonstrate that haemofungin causes swelling and lysis of growing fungal cells. It inhibits the growth of pathogenic Aspergillus, Candida, Fusarium and Rhizopus isolates at micromolar concentrations, while only weakly affecting the growth of mammalian cell lines. Genetic and biochemical analyses in A. nidulans and Aspergillus fumigatus indicate that haemofungin primarily inhibits ferrochelatase (HemH), the last enzyme in the haem biosynthetic pathway. Haemofungin was non-toxic and significantly reduced mortality rates of G. mellonella and D. melanogaster infected with A. fumigatus and Rhizopus oryzae, respectively.
  
  
  CONCLUSIONS
  Further development and in vivo validation of haemofungin is warranted.
authors.affiliation: Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: Dafna
authors.initials: D
authors.lastname: Ben Yaakov
authors.affiliation: Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: Anna
authors.initials: A
authors.lastname: Rivkin
authors.affiliation: Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Mircus
authors.affiliation: Department of Infectious Diseases, Infection Control and Employee Health, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Albert
authors.affiliation: Biocenter-Division of Molecular Biology, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Anna-Maria
authors.initials: AM
authors.lastname: Dietl
authors.affiliation: Raymond and Beverly Sackler School of Chemistry and Faculty of Exact Sciences, Tel-Aviv University, Ramat Aviv, Tel-Aviv 69978, Israel.
authors.forename: Dimitry
authors.initials: D
authors.lastname: Kovalerchick
authors.affiliation: Raymond and Beverly Sackler School of Chemistry and Faculty of Exact Sciences, Tel-Aviv University, Ramat Aviv, Tel-Aviv 69978, Israel.
authors.forename: Shmuel
authors.initials: S
authors.lastname: Carmeli
authors.affiliation: Biocenter-Division of Molecular Biology, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Hubertus
authors.initials: H
authors.lastname: Haas
authors.affiliation: Department of Infectious Diseases, Infection Control and Employee Health, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Dimitrios P
authors.initials: DP
authors.lastname: Kontoyiannis
authors.affiliation: Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel nosherov@post.tau.ac.il.
authors.forename: Nir
authors.initials: N
authors.lastname: Osherov
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D001233:Aspergillus nidulans / Q000187:drug effects / Q000235:genetics; D001419:Bacteria / Q000187:drug effects / Q000254:growth & development; D002460:Cell Line; D025141:Drug Resistance, Fungal; D004357:Drug Synergism; D005294:Ferrochelatase / Q000037:antagonists & inhibitors; D005658:Fungi / Q000187:drug effects / Q000254:growth & development; D006418:Heme / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology*; D006801:Humans; D007313:Insecta; D008826:Microbial Sensitivity Tests; D009181:Mycoses / Q000188:drug therapy / Q000382:microbiology; D011524:Protoporphyrins / Q000096:biosynthesis
chemical_list: D000935:Antifungal Agents; D006576:Heterocyclic Compounds, 4 or More Rings; D011524:Protoporphyrins; C000614193:haemofungin; D006418:Heme; C028025:protoporphyrin IX; D005294:Ferrochelatase