Abstract
The echinocandin (candin) class of antifungal drugs inhibit β – 1,3 – glucan synthase and block synthesis of β – 1,3 – glucan, an important polysaccharide in fungal cell walls. Candins are used widely for treatment of systemic infections caused by Candida and Aspergillus because of their high potency and low toxicity to humans. The incidence of candin resistance has been rare compared to that of azole resistance, although candin-resistant clinical isolates of C. albicans, C. glabrata, C. krusei and C. tropicalis have been reported in the USA and Europe in recent years. These isolates possess hundred – fold higher MIC values for candins than sensitive strains, as well as candin-resistant β – 1,3 – glucan synthase activities. Their candin resistance is associated with amino acid substitutions in the echinocandin resistant region (EchR) of the FKS gene that encodes a catalytic subunit of the β – 1,3 – glucan synthase. However, the effect of these amino acid substitutions on the drug-protein interaction and the molecular basis for the resistance is unknown. The exposure of fungi to candin drugs induces stress responses that activate networks involving transcriptional regulators and components controlling signal transduction of the pathways responsible for maintenance of fungal cell wall integrity. The fungal cell wall is still an attractive drug target and further investigation into the mechanisms of candin resistance and structural analysis of the β – 1,3 – glucan synthase protein complex will facilitate the development of broad spectrum inhibitors of fungal cell wall synthesis.
