Discovery of novel antifungal (1,3)-beta-D-glucan synthase inhibitors

The increasing incidence of life-threatening fungal infections has driven t he search for new, broad-spectrum fungicidal agents that can be used for tr eatment and prophylaxis in immunocompromised patients. Natural-product inhi bitors of cell wall (1,3)-beta-D-glucan synthase such as lipopeptide pneumo candins and echinocandins as well as the glycolipid papulacandins have been evaluated as potential therapeutics for the last two decades. As a result, MK-0991 (caspofungin acetate; Cancidas), a semisynthetic analogue of pneum ocandin B-o, is being developed as a broad-spectrum parenteral agent for th e treatment of aspergillosis and candidiasis. This and other lipopeptide an tifungal agents have limited oral bioavailability. Thus, we have sought new chemical structures with the mode of action of lipopeptide antifungal agen ts but with the potential for oral absorption. Results of natural-product s creening by a series of newly developed methods has Led to the identificati on of four acidic terpenoid (1,3)-beta-D-glucan synthase inhibitors. Of the four compounds, the in vitro antifungal activity of one, enfumafungin, is comparable to that of L-733560, a close analogue of MK-0991. Like the lipop eptides, enfumafungin specifically inhibits glucan synthesis in whole cells and in (1,3)-beta-D-glucan synthase assays, alters the morphologies of yea sts and molds, and produces a unique response in Saccharomyces cerevisiae s trains with point mutations in FKS1, the gene which encodes the Large subun it of glucan synthase.