Studies on the mechanism of antifungal action of aculeacin A

Aculeacin A was lethal for proliferating cultures of C. albicans. However, there was a paradoxical relationship between the drug concentration and the fungicidal activity; the lethal effect was greatest at levels of 0.08 to 1.25 microgram/ml and increases in the drug concentration above this range reduced its lethal effect. A similar anomalous dose-response patterns were also observed for the inhibitory effect of the drug on several cellular and subcellular biochemical activities. Association of this lethal effect of the drug was the formation of visible cell aggregates and the development of extremely huge forms in treated cultures. Aculeacin A induced osmotically fragile cells and viability of treated cultures was markedly reversed under high osmolarity. Tracer experiments and chemical analysis revealed that synthesis of alkali insoluble glucan was inhibited by the drug to a greater extent than synthesis of mannan and any other species of macromolecules, with resultant formation of alkali-insoluble glucan-deficient cells. Aculeacin A inhibited synthesis of beta-glucan from UDP-glucose catalyzed by cell-free extracts from C. albicans and S. cerevisiae. These data are consistent with the view that one of the principal target of aculeacin A action is on the beta-1,3-glucan synthetase reaction.