Modes of action of the new arylguanidine abafungin beyond interference with ergosterol biosynthesis and in vitro activity against medically important fungi

Abstract

Background: In contrast to the increasing numbers of agents for the treatment of invasive fungal infections, discoveries of new antifungal agents with therapeutic value in dermatomycoses are reported only rarely. Methods: Abafungin (chemical abstracts service registry No. 129639-79/8) is the first member of a novel class of synthetic antifungal compounds, the arylguanidines. It was first synthesized at Bayer AG, Leverkusen, Germany, and its antifungal action was discovered during the screening of H2-receptor antagonists based on the structure of famotidine. To obtain insight into its mode of action and antifungal activity, various tests were carried out with different fungal pathogensin vitro. Results: Abafungin was found to have potent antifungal activity. Furthermore, mode-of-action studies suggested that abafungin exerts its antifungal activity regardless of whether the pathogens are growing or in a resting state. One target of abafungin was found to be the inhibition of transmethylation at the C-24 position of the sterol side chain, catalyzed by the enzyme sterol-C-24-methyltransferase. A second action of abafungin seems to be a direct effect on the fungal cell membrane. Conclusion: The observed characteristics of abafungin indicate that abafungin might be a promising antifungal agent defining a new class of antimycotics. Copyright © 2008 S. Karger AG.