主催: The Japanese Society for Medical Mycology
Clinical isolates of Candida species with reduced susceptibility are rare. We have investigated the MCF resistance mechanism in C. glabrata clinical isolates and laboratory mutants. DNA sequence analysis of the ORFs encoding the β-1,3-glucan synthase catalytic subunits from sensitive and resistant clinical strains identified nucleotide changes that were predicted to cause a S629P amino acid change in the echinocandin resistance 'hot spot' of FKS2, and to introduce a premature stop codon in FKS1. As C. glabrata is haploid, one mutation in each of the two FKS genes may be required to confer full resistance to MCF. This hypothesis was tested by introducing the FKS2 S629P mutation in a sensitive strain using site-directed mutagenesis. The mutant had intermediate resistance to MCF, and developed elevated resistance when exposed to MCF. All resistant variants derived from the mutant showed the same MIC as the resistant clinical isolates, and each had either a predicted single amino acid change or a premature stop codon in FKS1. These findings indicate that functional homozygosity in glucan synthase subunits is required to confer clinically significant MCF resistance on C. glabrata.
