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Antimicrobial Agents and Chemotherapy, September 2009, p. 3690-3699, Vol. 53, No. 9
0066-4804/09/$08.00+0     doi:10.1128/AAC.00443-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Effect of Candida glabrata FKS1 and FKS2 Mutations on Echinocandin Sensitivity and Kinetics of 1,3-β-D-Glucan Synthase: Implication for the Existing Susceptibility Breakpoint{triangledown}

Guillermo Garcia-Effron,1 Samuel Lee,2 Steven Park,1 John D. Cleary,3 and David S. Perlin1*

Public Health Research Institute, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, New Jersey 07103,1 University of New Mexico and VA Albuquerque Medical Center, Albuquerque, New Mexico 87108,2 Mycotic Research Center, University of Mississippi Schools of Pharmacy and Medicine, Jackson, Mississippi3

Received 1 April 2009/ Returned for modification 16 May 2009/ Accepted 12 June 2009

Thirteen Candida glabrata strains harboring a range of mutations in hot spot regions of FKS1 and FKS2 were studied. The mutations were linked to an echinocandin reduced susceptibility phenotype. Sequence alignments showed that 11 out of the 13 mutants harbored a mutation in FKS1 or FKS2 not previously implicated in echinocandin reduced susceptibility in C. glabrata. A detailed kinetic characterization demonstrated that amino acid substitutions in Fks1p and Fks2p reduced drug sensitivity in mutant 1,3-β-D-glucan synthase by 2 to 3 log orders relative to that in wild-type enzyme. These mutations were also found to reduce the catalytic efficiency of the enzyme (Vmax) and to influence the relative expression of FKS genes. In view of the association of FKS mutations and reduced susceptibility of 1,3-β-D-glucan synthase, an evaluation of the new CLSI echinocandin susceptibility breakpoint was conducted. Only 3 of 13 resistant fks mutants (23%) were considered anidulafungin or micafungin nonsusceptible (MIC > 2 µg/ml) by this criterion. In contrast, most fks mutants (92%) exceeded a MIC of >2 µg/ml with caspofungin. However, when MIC determinations were performed in the presence of 50% serum, all C. glabrata fks mutants showed MICs of ≥2 µg/ml for the three echinocandin drugs. As has been observed with Candida albicans, the kinetic inhibition parameter 50% inhibitory concentration may be a better predictor of FKS-mediated resistance. Finally, the close association between FKS1/FKS2 hot spot mutations provides a basis for understanding echinocandin resistance in C. glabrata.

* Corresponding author. Mailing address: Public Health Research Institute, 225 Warren Street, Newark, NJ 07103. Phone: (973) 854-3200. Fax: (973) 854-3101. E-mail: perlinds{at}umdnj.edu

{triangledown} Published ahead of print on 22 June 2009.

Antimicrobial Agents and Chemotherapy, September 2009, p. 3690-3699, Vol. 53, No. 9
0066-4804/09/$08.00+0     doi:10.1128/AAC.00443-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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