Dafna Ben-Yaakov

Dimitrios P. Kontoyiannis

Dodo Chikvashvili

Gabriel Mircus

Nathaniel Albert

Nir Osherov

Yona Shadkchan

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-
            c
            hloro-6-
            a
            rylamino-7-
            n
            itro-
            be
            nzo
            f
            urazane (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.
          </jats:p

Crossref

Antimicrobial Agents and Chemotherapy

Identification and Characterization of a Novel Family of Selective Antifungal Compounds (CANBEFs) That Interfere with Fungal Protein Synthesis

Identification and Characterization of a Novel Family of Selective Antifungal Compounds (CANBEFs) That Interfere with Fungal Protein Synthesis

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