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.

Two spontaneous triadimefon-resistant mutants of Ustilago maydis, 151ar/l and 151ar/3, were investigated with regard to their extent of crossresistance and their sterol composition to elicit indications about the specificity of the present resistance mechanisms. Testing resistance to various sterol biosynthesis inhibitors and toxicants with different modes of action, it could be demonstrated that, in the mutant 151ar/l, cross-resistance was limited to the sterol demethylation inhibitors (DMIs), whereas, in strain 151ar/3, resistance included most sterol biosynthesis inhibitors studied (DMIs, morpholines, piperidines, allylamines) as well as the unrelated compounds vinclozolin and cycloheximide. Sterol analyses showed that both mutants contained ergosterol as the main sterol component. In comparison with the sensitive reference strain, the mutant 151ar/l had a slightly elevated content of C-14 methyl sterols, whereas in strain 151ar/3 the amount of ergosterol was increased. Triadimefon caused an accumulation of C-14 methyl sterols and a decrease in ergosterol content in the sensitive strain and the mutant 151ar/l, whereas the other strain 151ar/3 remained unaffected. The results indicate that several resistance mechanisms are probably operating in the two mutants.

Biochemical studies on mode of action enable the chemist to optimize biologically active chemical structures. As a case study we describe the optimization process of fungicides inhibiting sterol biosynthesis. The spiroketalamines obtained represent new chemicals with various modes of action on sterol biosynthesis. These examples demonstrate that biochemixal studies allow directed pesticide design. The value of biochemistry in pesticide discovery has to be seen in a stepwise optimization rather than in "de-novo"-design.

Two spontaneous triadimefon‐resistant mutants of Ustilago maydis, 151ar/1 and 151ar/3, were investigated with regard to their extent of cross‐resistance and their sterol composition to elicit indications about the specificity of the present resistance mechanisms. Testing resistance to various sterol biosynthesis inhibitors and toxicants with different modes of action, it could be demonstrated that, in the mutant 151ar/1, cross‐resistance was limited to the sterol demethylation inhibitors (DMIs), whereas, in strain 151ar/3, resistance included most sterol biosynthesis inhibitors studied (DMIs, morpholines, piperidines, allylamines) as well as the unrelated compounds vinclozolin and cycloheximide. Sterol analyses showed that both mutants contained ergosterol as the main sterol component. In comparison with the sensitive reference strain, the mutant 151ar/1 had a slightly elevated content of C‐14 methyl sterols, whereas in strain 151ar/3 the amount of ergosterol was increased. Triadimefon caused an accumulation of C‐14 methyl sterols and a decrease in ergosterol content in the sensitive strain and the mutant 151ar/1, whereas the other strain 151ar/3 remained unaffected. The results indicate that several resistance mechanisms are probably operating in the two mutants.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.