Oxathiin carboxamides highly active against carboxin-resistant succinic dehydrogenase complexes from carboxin-selected mutants of Ustilago maydis and Aspergillus nidulans

Abstract

The systemic fungicide carboxin (5,6-dihydro-2-methyl-1,4-oxathiin-3-carboxanilide) and structurally related analogs are powerful inhibitors of succinate oxidation in mitochondria isolated from a variety of sources. The site of action which is, apparently, also that for thenoyltrifluoracetone, is in the complex II (succinate-ubiquinone reductase) region of the mitochondrial electron transfer chain. The succinic dehydrogenase complex (SDC) in mitochondria from carbon-resistant mutant strains of Ustilago maydis and Aspergillus nidulans is resistant to the fungicide in vitro. The current study shows that certain oxathiin carboxamides are selectively active against particular mutated SDCs of U. maydis and A. nidulans. Molecular structures affecting the phenotypic expression of mutation to carboxin resistance in U. maydis do not appear to affect similarly such expression in A. nidulans and vice versa. Of particular interest was the discovery of oxathiin carboxamides, e.g., 4′-phenylcarboxin, which were more inhibitory to the enzyme complex from one category of carboxin-resistant mutants of U. maydis than from the wild-type strain. Although such negative correlation between carboxin and other carboxin analogs has not been observed in studies with other categories of mutants, structures which drastically lower the resistance level were found in all cases. It appears that for any given mutation affecting carboxin sensitivity of the SDC in fungi, a specific structural group of carboxamides (or even a specific carboxamide) may be found which will alleviate or reverse the effect of the mutation in terms of inhibition of the SDC. If the mutations alter a protein receptor site for carboxamides, such mutations might be expected to influence the binding of carboxins of different structure. In essence, then, different molecular structures can “recognize” different alterations in the mutated enzyme complex and inhibit effectively. With few exceptions, the inhibition by carboxamides of cell growth of wild-type and carboxin-resistant strains of U. maydis and A. nidulans closely paralleded the inhibition of their respective SDCs. Although the few analogs tested were found unable to control corn smut systemically in seedlings artificially inoculated with compatible carboxin-resistant strains, control of naturally occurring carboxin-resistant strains of pathogenic fungi may be possible using particular structural analogs of carboxin which selectively inhibit the mutant organisms.