Inhibition of calcineurin as a strategy for biofilm control: Trichosporon spp. as a case study

Area of Science:

• Mycology
• Infectious Diseases
• Biochemistry

Background:

• Opportunistic fungal pathogens, Trichosporon spp., cause high-mortality invasive fungal infections (IFIs) in immunocompromised patients.
• Trichosporon spp. exhibit intrinsic resistance to echinocandins and tolerance to polyenes and triazoles, particularly in biofilms.
• Antifungal resistance in Trichosporon biofilms poses a significant clinical challenge.

Purpose of the Study:

• To investigate the impact of calcineurin inhibition on the development and antifungal tolerance of Trichosporon biofilms.
• To evaluate Ciclosporin A (CsA) as a calcineurin inhibitor for targeting Trichosporon biofilms.
• To elucidate the molecular mechanism of CsA interaction with Trichosporon calcineurin.

Main Methods:

• Treatment of mature Trichosporon biofilms (T. inkin and T. asahii) with Ciclosporin A (CsA).
• Analysis of biofilm biomass, metabolic activity, ultrastructure, and susceptibility to antifungals.
• Molecular docking studies to assess CsA binding to T. asahii calcineurin.

Main Results:

• CsA significantly reduced Trichosporon biofilm biomass and metabolic activity.
• Biofilms developed in the presence of CsA exhibited increased susceptibility to conventional antifungals.
• CsA induced structural alterations in the biofilms and molecular modeling indicated CsA blocks calcineurin active site.

Conclusions:

• Calcineurin inhibition by CsA is a promising strategy to combat antifungal-resistant Trichosporon biofilms.
• Targeting calcineurin can overcome antifungal tolerance in these opportunistic fungal pathogens.
• This approach may improve treatment outcomes for invasive fungal infections caused by Trichosporon spp.