Identification and characterization of haemofungin, a novel antifungal compound that inhibits the final step of haem biosynthesis

Dafna Ben Yaakov, Anna Rivkin, Gabriel Mircus, Nathaniel Albert, Anna Maria Dietl, Dimitry Kovalerchick, Shmuel Carmeli, Hubertus Haas, Dimitrios P. Kontoyiannis, Nir Osherov

Research output: Contribution to journalArticlepeer-review

Abstract

Objectives: 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.

Original languageEnglish
Pages (from-to)946-952
Number of pages7
JournalJournal of Antimicrobial Chemotherapy
Volume71
Issue number4
DOIs
StatePublished - 1 Apr 2016

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