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Candida albicans Biofilm Chip CaBChip for High-throughput Antifungal Drug Screening
Published on: July 18, 2012
AFM combined to ATR-FTIR reveals Candida cell wall changes under caspofungin treatment
Fabienne Quilès1, Isabelle Accoceberry, Célia Couzigou
1CNRS, Laboratoire de Chimie Physique et Microbiologie pour l'Environnement, LCPME, UMR 7564, Villers-lès-Nancy, F-54600, France. elkirat1@univ-lorraine.fr.
Abstract:
Fungal pathogens from Candida genus are responsible for severe life-threatening infections and the antifungal arsenal is still limited. Caspofungin, an antifungal drug used for human therapy, acts as a blocking agent of the cell wall synthesis by inhibiting the β-1,3-glucan-synthase encoded by FKS genes. Despite its efficiency, the number of genetic mutants that are resistant to caspofungin is increasing. An important challenge to improve antifungal therapy is to understand cellular phenomenon that are associated with drug resistance. Here we used atomic force microscopy (AFM) combined to Fourier transform infrared spectroscopy in attenuated total reflection mode (ATR-FTIR) to decipher the effect of low and high drug concentration on the morphology, mechanics and cell wall composition of two Candida strains, one susceptible and one resistant to caspofungin. Our results confirm that caspofungin induces a dramatic cell wall remodelling via activation of stress responses, even at high drug concentration. Additionally, we highlighted unexpected changes related to drug resistance, suggesting that caspofungin resistance associated with FKS gene mutations comes from a combination of effects: (i) an overall remodelling of yeast cell wall composition; and (ii) cell wall stiffening through chitin synthesis. This work demonstrates that AFM combined to ATR-FTIR is a valuable approach to understand at the molecular scale the biological mechanisms associated with drug resistance.
Insights
Caspofungin resistance in Candida involves cell wall remodeling and increased chitin synthesis. Advanced microscopy reveals molecular mechanisms underlying antifungal drug resistance.
Area of Science:
- Mycology and Infectious Diseases
- Biophysics and Molecular Biology
- Antifungal Drug Resistance Mechanisms
Background:
- Candida species cause life-threatening infections, with limited antifungal options.
- Caspofungin inhibits fungal cell wall synthesis via FKS gene targets.
- Increasing caspofungin resistance necessitates understanding resistance mechanisms.
Purpose of the Study:
- To investigate the effects of caspofungin on Candida cell wall morphology, mechanics, and composition.
- To elucidate the cellular phenomena associated with caspofungin resistance.
- To evaluate the utility of AFM and ATR-FTIR in studying antifungal resistance.
Main Methods:
- Utilized Atomic Force Microscopy (AFM) for morphology and mechanics.
- Employed Fourier Transform Infrared Spectroscopy (ATR-FTIR) for cell wall composition analysis.
- Compared susceptible and resistant Candida strains under varying caspofungin concentrations.
Main Results:
- Caspofungin induced significant cell wall remodeling and stress responses in both susceptible and resistant strains.
- Identified altered cell wall composition and increased chitin synthesis in caspofungin-resistant strains.
- Observed cell wall stiffening as a key factor in caspofungin resistance.
Conclusions:
- AFM and ATR-FTIR are powerful tools for molecular-level analysis of antifungal resistance.
- Caspofungin resistance in Candida involves complex adaptations in cell wall structure and synthesis.
- Understanding these mechanisms is crucial for developing improved antifungal therapies.
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