Physiological factors influencing the antifungal activity of zopfiellin

Zopfiellin, a novel cyclooctanoid natural product isolated from Zopfiella curvata No. 37-3, was evaluated for antifungal activity and its mechanism of action was investigated. Fungal growth inhibition caused by zopfiellin was mediated by the pH of the growth medium. Maximum inhibitory activity was obtained between pH 5 and 5.5. Intramolecular ring closure of zopfiellin from a tetracarboxylate to an anhydride form occurring at pH below 6 is apparently required for uptake by the fungus. Biological activity of zopfiellin could be reversed by exogenous addition of oxaloacetate under both glycolytic and gluconeogenic growth conditions. The in vitro activity of zopfiellin was tested on the enzyme phosphoenolpyruvate carboxykinase, a regulatory enzyme in the gluconeogenesis pathway catalyzing the conversion of oxaloacetate to phosphoenolpyruvate. The mechanism of antifungal activity of zopfiellin appears to be associated with physiological processes involving oxaloacetate metabolism.