Echinocandins: Resistance Mechanisms
Santosh Katiyar and Thomas Edlind
from: Antifungals: From Genomics to Resistance and the Development of Novel Agents (Edited by: Alix T. Coste and Patrick Vandeputte). Caister Academic Press, U.K. (2015) Pages: 55-70.
Abstract
Echinocandins, including caspofungin, micafungin, and anidulafungin are semi-synthetic lipopeptides that inhibit β-1,3-glucan synthase and hence fungal cell wall synthesis. They display excellent to moderate activity versus most Candida and Aspergillus species, although acquired resistance increasingly compromises their use versus C. glabrata. A primary limitation is the intrinsic resistance of all other fungal pathogens. Genetic analysis of acquired resistance in Saccharomyces cerevisiae identified the integral membrane protein Fks1 as the echinocandin target. Mutations cluster into hot spots 1 and, less commonly, 2 and 3 which share a similar topology: within or adjacent to the outer leaflet of the plasma membrane, and flanking a central cytoplasmic domain containing the likely substrate binding and catalytic sites. The differential resistance demonstrated by certain Fks1 mutations is consistent with direct interaction between the mutated residues and echinocandin-specific side chains. Differential resistance is also conferred by sphingolipid biosynthesis pathway mutations, suggesting a tripartite model for echinocandin-Fks1-membrane interaction. Analysis of Fks1 hot spot regions from fungi that exhibit intrinsically reduced susceptibility (Candida parapsilosis) or resistance (including Fusarium and Scedosporium species) identified substitutions that are likely to contribute to those phenotypes. Additional contributors likely include a reduced role for β-1,3-glucan in intrinsically resistant fungi, and increased cell wall chitin or melanin. Support for these Fks1-independent mechanisms is provided by dimorphic fungi such as Histoplasma capsulatum that encode a single Fks1 but alternate between echinocandin susceptible and resistant in their hyphal and yeast phases, respectively read more ...
