Login / Signup

Echinocandin Resistance in Aspergillus fumigatus Has Broad Implications for Membrane Lipid Perturbations That Influence Drug-Target Interactions.

Shruthi SatishDavid S Perlin
Published in: Microbiology insights (2019)
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.
Keyphrases
  • reactive oxygen species
  • cell wall
  • cell death
  • candida albicans
  • stem cells
  • drug induced
  • fatty acid
  • transcription factor
  • gene expression
  • cystic fibrosis
  • dna methylation
  • high glucose
  • endoplasmic reticulum