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Antimicrobial Agents and Chemotherapy, August 2005, p. 3264-3273, Vol. 49, No. 8
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.8.3264-3273.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Specific Substitutions in the Echinocandin Target Fks1p Account for Reduced Susceptibility of Rare Laboratory and Clinical Candida sp. Isolates

S. Park,1,{dagger} R. Kelly,2,{dagger} J. Nielsen Kahn,2,{dagger} J. Robles,1 M.-J. Hsu,2 E. Register,2 W. Li,2 V. Vyas,2 H. Fan,2 G. Abruzzo,2 A. Flattery,2 C. Gill,2 G. Chrebet,2 S. A. Parent,2 M. Kurtz,2 H. Teppler,2 C. M. Douglas,2 and D. S. Perlin1*

Public Health Research Institute, 225 Warren Street, Newark, New Jersey 07103,1 Merck Research Laboratories, Rahway, New Jersey 070652

Received 11 February 2005/ Returned for modification 21 March 2005/ Accepted 30 April 2005

An association between reduced susceptibility to echinocandins and changes in the 1,3-ß-D-glucan synthase (GS) subunit Fks1p was investigated. Specific mutations in fks1 genes from Saccharomyces cerevisiae and Candida albicans mutants are described that are necessary and sufficient for reduced susceptibility to the echinocandin drug caspofungin. One group of amino acid changes in ScFks1p, ScFks2p, and CaFks1p defines a conserved region (Phe 641 to Asp 648 of CaFks1p) in the Fks1 family of proteins. The relationship between several of these fks1 mutations and the phenotype of reduced caspofungin susceptibility was confirmed using site-directed mutagenesis or integrative transformation. Glucan synthase activity from these mutants was less susceptible to caspofungin inhibition, and heterozygous and homozygous Cafks1 C. albicans mutants could be distinguished based on the shape of inhibition curves. The C. albicans mutants were less susceptible to caspofungin than wild-type strains in a murine model of disseminated candidiasis. Five Candida isolates with reduced susceptibility to caspofungin were recovered from three patients enrolled in a clinical trial. Four C. albicans strains showed amino acid changes at Ser 645 of CaFks1p, while a single Candida krusei isolate had a deduced R1361G substitution. The clinical C. albicans mutants were less susceptible to caspofungin in the disseminated candidiasis model, and GS inhibition profiles and DNA sequence analyses were consistent with a homozygous fks1 mutation. Our results indicate that substitutions in the Fks1p subunit of GS are sufficient to confer reduced susceptibility to echinocandins in S. cerevisiae and the pathogens C. albicans and C. krusei.

* Corresponding author. Mailing address: Public Health Research Institute, 225 Warren St., Newark, NJ 07103. Phone: (973) 854-3200. Fax: (973) 854-3101. E-mail: perlin{at}phri.org.

{dagger} S.P., R.K., and J.N.K. contributed equally to this work.

Antimicrobial Agents and Chemotherapy, August 2005, p. 3264-3273, Vol. 49, No. 8
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.8.3264-3273.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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