Author:

Gardiner RE, Souteropoulos P, Park S, Perlin DS

Date: 7 September 2005

Abstract:

Caspofungin acetate (CAS) is a member of a new class of clinically-approvedechinocandin drugs to treat invasive aspergillosis. CAS inhibits the activity ofb-1,3-D-glucan synthase (GS), thus damaging the fungal cell wall. Although noclinical resistance of Aspergillus to CAS has been reported as yet, the developmentof in vitro reduced susceptibility is presumed to be inevitable. By contrast,echinocandin resistance in laboratory strains of Candida albicans and Saccharomycescerevisiae has been well documented. To study the potential for clinicalresistance in Aspergillus, two classes of Aspergillus fumigatus mutant strains wereisolated that exhibited reduced susceptibility to CAS. In the first class, a sitedirectedmutation within the target gene (AfFKS1, encoding the putative catalyticsubunit of GS) was introduced and shown to confer low-level (16-fold) reducedsusceptibility. A second class of spontaneous mutants were sensitive to low levels ofdrug but displayed nearly normal growth above 0.5 mg/ml, suggesting induction ofan unknown resistance mechanism. At higher levels of drug (]/16 mg/ml), themutants displayed partially restored sensitivity. Preliminary studies indicate thatneither target site mutations, nor changes in target gene expression are present inthese strains, as has been documented for several yeasts. Instead, preliminaryresults indicate that the molecular mechanism(s) underlying reduced susceptibility of CAS in the A. fumigatus strains is novel, possibly due to remodeling of the cell wall components.

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