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Antimicrobial Agents and Chemotherapy, February 2000, p. 368-377, Vol. 44, No. 2
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Discovery of Novel Antifungal (1,3)-beta -D-Glucan Synthase Inhibitors

J. Onishi,1,* M. Meinz,1 J. Thompson,1 J. Curotto,1 S. Dreikorn,1 M. Rosenbach,1 C. Douglas,1 G. Abruzzo,1 A. Flattery,1 L. Kong,1 A. Cabello,2 F. Vicente,2 F. Pelaez,2 M. T. Diez,2 I. Martin,2 G. Bills,3 R. Giacobbe,3 A. Dombrowski,3 R. Schwartz,3 S. Morris,3 G. Harris,3 A. Tsipouras,3 K. Wilson,3 and M. B. Kurtz1

Departments of Infectious Diseases1 and Natural Products Drug Discovery,3 Merck Research Laboratories, Rahway, NJ 07065-0900,3 and Centro de Investigación Básica-Natural Products Drug Discovery,2 MSD-Spain, Madrid 28027, Spain2

Received 7 September 1999/Returned for modification 25 October 1999/Accepted 10 November 1999

The increasing incidence of life-threatening fungal infections has driven the search for new, broad-spectrum fungicidal agents that can be used for treatment and prophylaxis in immunocompromised patients. Natural-product inhibitors of cell wall (1,3)-beta -D-glucan synthase such as lipopeptide pneumocandins 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 pneumocandin Bo, is being developed as a broad-spectrum parenteral agent for the treatment of aspergillosis and candidiasis. This and other lipopeptide antifungal agents have limited oral bioavailability. Thus, we have sought new chemical structures with the mode of action of lipopeptide antifungal agents but with the potential for oral absorption. Results of natural-product screening by a series of newly developed methods has led to the identification 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 lipopeptides, enfumafungin specifically inhibits glucan synthesis in whole cells and in (1,3)-beta -D-glucan synthase assays, alters the morphologies of yeasts and molds, and produces a unique response in Saccharomyces cerevisiae strains with point mutations in FKS1, the gene which encodes the large subunit of glucan synthase.

* Corresponding author. Mailing address: Department of Infectious Diseases, Merck Research Laboratories, R80Y-225 Infectious Diseases, P.O. Box 2000, Rahway, NJ 07065-0900. Phone: (732) 594-5515. Fax: (732) 594-1399. E-mail: jan_onishi{at}merck.com.

Antimicrobial Agents and Chemotherapy, February 2000, p. 368-377, Vol. 44, No. 2
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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