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Biomimetic Materials to Characterize Bacteria-host Interactions
Published on: November 16, 2015
Multivalent Fucosides Targeting β-Propeller Lectins from Lung Pathogens with Promising Anti-Adhesive Properties
Margherita Duca1,2,3, Diksha Haksar1, Jacq van Neer2
1Department of Chemical Biology & Drug Discovery, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, NL-3508 TB Utrecht, The Netherlands.
Abstract:
Fungal and bacterial pathogens causing lung infections often use lectins to mediate adhesion to glycoconjugates at the surface of host tissues. Given the rapid emergence of resistance to the treatments in current use, β-propeller lectins such as FleA from Aspergillus fumigatus, SapL1 from Scedosporium apiospermum, and BambL from Burkholderia ambifaria have become appealing targets for the design of anti-adhesive agents. In search of novel and cheap anti-infectious agents, we synthesized multivalent compounds that can display up to 20 units of fucose, the natural ligand. We obtained nanomolar inhibitors that are several orders of magnitude stronger than their monovalent analogue according to several biophysical techniques (i.e., fluorescence polarization, isothermal titration calorimetry, and bio-layer interferometry). The reason for high affinity might be attributed to a strong aggregating mechanism, which was examined by analytical ultracentrifugation. Notably, the fucosylated inhibitors reduced the adhesion of A. fumigatus spores to lung epithelial cells when administered 1 h before or after the infection of human lung epithelial cells. For this reason, we propose them as promising anti-adhesive drugs for the prevention and treatment of aspergillosis and related microbial lung infections.
Insights
Novel multivalent fucose compounds were developed as potent anti-adhesion agents against lung infections. These inhibitors show promise for treating aspergillosis and other microbial lung diseases.
Area of Science:
- Microbiology
- Biochemistry
- Drug Discovery
Background:
- Fungal and bacterial lung pathogens utilize lectins for host tissue adhesion.
- Emerging drug resistance necessitates novel anti-infective strategies.
- Beta-propeller lectins (e.g., FleA, SapL1, BambL) are key targets for anti-adhesion agents.
Purpose of the Study:
- To synthesize and evaluate novel multivalent compounds as anti-adhesion agents.
- To investigate the inhibitory potential of fucose-displaying compounds against microbial lung infections.
- To identify cost-effective alternatives to current anti-infective treatments.
Main Methods:
- Synthesis of multivalent compounds displaying fucose ligands.
- Affinity and binding kinetics assessed by fluorescence polarization, isothermal titration calorimetry, and bio-layer interferometry.
- Aggregation mechanisms studied using analytical ultracentrifugation.
- Inhibition of Aspergillus fumigatus spore adhesion to lung epithelial cells.
Main Results:
- Synthesized multivalent fucose compounds demonstrated nanomolar inhibitory activity, significantly exceeding monovalent analogs.
- High affinity is potentially linked to a strong aggregating mechanism.
- Fucosylated inhibitors effectively reduced fungal spore adhesion to human lung epithelial cells.
- Inhibitors were effective when administered both before and after infection.
Conclusions:
- Multivalent fucosylated compounds are potent inhibitors of microbial adhesion.
- These compounds represent promising candidates for anti-adhesive drugs against aspergillosis and related lung infections.
- The findings support the development of novel, cost-effective anti-infective therapies.
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