title: Identification and characterization of a novel family of selective antifungal compounds (CANBEFs) that interfere with fungal protein synthesis.
abstract: Invasive mycotic infections have become more common during recent decades, posing an increasing threat to public health. However, despite the growing needs, treatments for invasive fungal infections remain unsatisfactory and are limited to a small number of antifungals. The aim of this study was to identify novel fungal cell wall inhibitors from a library of small chemical compounds using a conditional protein kinase C (PKC)-expressing strain of Aspergillus nidulans sensitive to cell wall-active agents. Eight "hit" compounds affecting cell wall integrity were identified from a screen of 35,000 small chemical compounds. Five shared a common basic molecular structure of 4-chloro-6-arylamino-7-nitro-benzofurazane (CANBEF). The most potent compound, CANBEF-24, was characterized further and was shown to inhibit the growth of pathogenic Aspergillus, Candida, Fusarium, and Rhizopus isolates at micromolar concentrations but not to affect the growth of mammalian cell lines. CANBEF-24 demonstrated strong synergy in combination with caspofungin, an antifungal that inhibits cell wall biosynthesis. Genetic and biochemical analyses with Aspergillus nidulans and Saccharomyces cerevisiae indicated that CANBEFs selectively inhibit fungal rRNA maturation and protein synthesis, suggesting that their effect on the cell wall is indirect. CANBEFs were nontoxic in insect (Galleria mellonella, Drosophila melanogaster) and mouse models of fungal infection. Preliminary evidence showing no therapeutic benefit in these models suggests that further cycles of optimization are needed for the development of this novel class of compounds for systemic use.
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, Texas, USA.
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Albert
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 Physiology and Pharmacology, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: Dodo
authors.initials: D
authors.lastname: Chikvashvili
authors.affiliation: Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: Yona
authors.initials: Y
authors.lastname: Shadkchan
authors.affiliation: Department of Infectious Diseases, Infection Control and Employee Health, University of Texas MD Anderson Cancer Center, Houston, Texas, 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*; D001230:Aspergillus / Q000187:drug effects / Q000378:metabolism; D002175:Candida / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D004331:Drosophila melanogaster / Q000187:drug effects; D005260:Female; D005656:Fungal Proteins / Q000378:metabolism*; D005670:Fusarium / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051379:Mice; D008813:Mice, Inbred ICR; D008826:Microbial Sensitivity Tests; D014176:Protein Biosynthesis / Q000187:drug effects; D012233:Rhizopus / Q000187:drug effects / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000378:metabolism
chemical_list: D000935:Antifungal Agents; D005656:Fungal Proteins