The Paradoxical Effect of Echinocandins in Aspergillus fumigatus Relies on Recovery of the beta-1,3-Glucan Synthase Fks1

Loiko, Veronika und Wagener, Johannes (2017): The Paradoxical Effect of Echinocandins in Aspergillus fumigatus Relies on Recovery of the beta-1,3-Glucan Synthase Fks1. In: Antimicrobial Agents and Chemotherapy, Bd. 61, Nr. 2, e01690-16

Abstract

Echinocandins target the fungal cell wall by inhibiting biosynthesis of the cell wall carbohydrate beta-1,3-glucan. This antifungal drug class exhibits a paradoxical effect that is characterized by the resumption of growth of otherwise susceptible strains at higher drug concentrations (approximately 4 to 32 mu g/ml). The nature of this phenomenon is still unknown. In this study, we analyzed the paradoxical effect of the echinocandin caspofungin on the pathogenic mold Aspergillus fumigatus. Using a conditional fks1 mutant, we show that very high caspofungin concentrations exert an additional antifungal activity besides inhibition of the beta-1,3-glucan synthase. This activity could explain the suppression of paradoxical growth at very high caspofungin concentrations. Additionally, we found that exposure to inhibitory caspofungin concentrations always causes initial growth deprivation independently of the capability of the drug concentration to induce the paradoxical effect. Paradoxically growing hyphae emerge from microcolonies essentially devoid of beta-1,3-glucan. However, these hyphae expose beta-1,3-glucan again, suggesting that beta-1,3-glucan synthesis is restored. In agreement with this hypothesis, we found that expression of the beta-1,3-glucan synthase Fks1 is an essential requirement for the paradoxical effect. Surprisingly, overexpression of fks1 renders A. fumigatus more susceptible, whereas reduced expression leads to hyphae that are more resistant to the growth-inhibitory and limited fungicidal activity of caspofungin. Upregulation of chitin synthesis appears to be of minor importance for the paradoxical effect, since paradoxically growing hyphae exhibit significantly less chitin than the growth- deprived parental microcolonies. Our results argue for a model where the paradoxical effect primarily relies on recovery of beta-1,3-glucan synthase activity.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 0066-4804
• Sprache: Englisch