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Antimicrobial Agents and Chemotherapy, July 2005, p. 2851-2856, Vol. 49, No. 7
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.7.2851-2856.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Cryptococcus neoformans Resistance to Echinocandins: (1,3)ß-Glucan Synthase Activity Is Sensitive to Echinocandins

Marybeth A. Maligie and Claude P. Selitrennikoff*

University of Colorado Health Sciences Center, Department of Cell and Developmental Biology, 12635 E. Montview Blvd., Suite 215, Aurora, Colorado 80010

Received 9 December 2004/ Returned for modification 16 January 2005/ Accepted 2 April 2005

(1,3)ß-D-Glucan synthase (EC 2.4.1.34. UDP-glucose: 1,3-ß-D-glucan 3-ß-glucosyltransferase) uses UDP-glucose as substrate and catalyzes the polymerization of glucose ([1,3]-ß-linkages) to form the major carbohydrate component of the fungal cell wall. We have optimized in vitro assay conditions for (1,3)ß-glucan synthase activity from Cryptococcus neoformans. Cells lysed in 50 mM Tris, pH 7.75, containing 20% glycerol, 2 mM NaF, 1 mM dithiothreitol, 0.1 mM phenylmethylsulfonyl fluoride, 5 mM MgCl2, 0.1% protease and phosphatase inhibitor cocktails, and 60 µM GTP{gamma}S produced maximum specific activity in vitro. We tested in vitro C. neoformans (1,3)ß-glucan synthase activity against the (1,3)ß-glucan synthase inhibitors, caspofungin and cilofungin, and have determined that (1,3)ß-glucan synthase activity is very sensitive (apparent Ki of 0.17 ± 0.02 µM and 22 ± 5.7 µM, respectively) to these echinocandins. Taken together with high MICs for C. neoformans (caspofungin MIC, 16 µg/ml; cilofungin MIC, 64 µg/ml), our results indicate that C. neoformans is resistant to caspofungin and cilofungin by a mechanism(s) unrelated to (1,3)ß-glucan synthase resistance.

* Corresponding author. Mailing address: University of Colorado Health Sciences Center, Department of Cell and Developmental Biology, 12635 E. Montview Blvd., Suite 215, Aurora, CO 80010. Phone: (303) 724-3426. Fax: (303) 724-0861. E-mail: Claude.Selitrennikoff{at}uchsc.edu

Antimicrobial Agents and Chemotherapy, July 2005, p. 2851-2856, Vol. 49, No. 7
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.7.2851-2856.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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