Homoserine dehydrogenase as a selective target molecule for antifungal action

Abstract

Remarkable progress has been made recently in antifungal chemotherapy with the advent of imidazole-or triazole-containing antifungal drugs. However, their clinical usefulness appears to be limited by insufficiency of the selective toxicity. This is probably ascribable to the fact that both fungal and human cells share the common target molecule for attack of azoles, cytochrome P-450, although the affinity of recently developed triazoles such as itraconazole and fluconazole with this enzyme from fungal cells is much higher than that from host cells (Vanden Bossche et al., 1989). It should be those enzymes which are of vital importance for fungal growth but absent in human cells that provides the potential target for higher selectivity of an antifungal action. In the last decade, our laboratory has been involved, in collaboration with several other research groups, in the search for and preclinical evaluation of new antifungal compounds with a favorable profile of activity and safety. In the course of rather empirical screening of antifungal antibiotics with microbial culture filtrates, we discovered a couple of novel ones considered to be promising candidates or leads for clinically useful drugs. Among them is an antibiotic with aspartate-related structure, (s)2-amino-4-oxo-5-hydroxypentanoic acid (RI-331) (Fig. 1).