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  • Title: Echinocandin Resistance in Aspergillus fumigatus Has Broad Implications for Membrane Lipid Perturbations That Influence Drug-Target Interactions.
    Author: Satish S, Perlin DS.
    Journal: Microbiol Insights; 2019; 12():1178636119897034. PubMed ID: 35185336.
    Abstract:
    Echinocandin drugs target the fungal enzyme β-(1,3)-glucan synthase (GS), which is required for the synthesis of cell wall component β-(1,3)-d-glucan. They are first-line therapy for Candida infections but are increasingly used as second-line therapy for Aspergillus infections. Resistance to echinocandins has been mainly studied in Candida and occurs due to mutations in FKS genes encoding GS. In our recent report, we identified a novel mechanism of echinocandin resistance in Aspergillus fumigatus. We showed that caspofungin exposure modifies GS, rendering it insensitive to echinocandins. This mechanism of resistance involved alteration of the GS lipid microenvironment and was mediated via an off-target effect on mitochondria leading to increased reactive oxygen species (ROS). We hypothesized that caspofungin-induced ROS alters the lipid composition around GS, changing its conformation and making it insensitive to echinocandins. In this commentary, we review both fks1-dependent and fks1-independent mechanisms of echinocandin resistance in A fumigatus. We believe this new resistance mechanism is also conserved among Candida spp. with implications for drug tolerance and/or resistance. Furthermore, we propose that ROS acts as a signaling molecule regulating lipid biogenesis, which impacts the structure-function of membrane proteins with implications for other types of drug-target interactions.
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