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Efficient and Site-specific Antibody Labeling by Strain-promoted Azide-alkyne Cycloaddition
Published on: December 23, 2016
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Ribosome-Templated Azide-Alkyne Cycloadditions: Synthesis of Potent Macrolide Antibiotics by In Situ Click Chemistry
Ian Glassford1, Christiana N Teijaro1, Samer S Daher1
1Department of Chemistry, Temple University , Philadelphia, Pennsylvania 19122, United States.
Journal of the American Chemical Society
|February 16, 2016
Summary
This study developed a novel in situ click chemistry method to synthesize and discover new antibiotics targeting bacterial ribosomes. This approach efficiently identifies potent drug candidates with low toxicity.
Area of Science:
- Medicinal Chemistry
- Molecular Biology
- Drug Discovery
Background:
- Bacterial ribosomes are crucial drug targets, with over half of antibiotics acting on them.
- Macrolide antibiotics inhibit protein synthesis by binding to the 50S ribosomal subunit.
- Solithromycin is a third-generation macrolide antibiotic.
Purpose of the Study:
- To develop a ribosome-templated in situ click chemistry method for synthesizing novel macrolide antibiotics.
- To expand this method from binary to multi-component reactions (up to 16 components).
- To evaluate the potency and therapeutic index of synthesized compounds.
Main Methods:
- In situ click chemistry using macrolide-functionalized azides and various alkynes on E. coli ribosomes or 50S subunits.
- Site-Identification by Ligand Competitive Saturation (SILCS) for computational analysis of ligand-ribosome interactions.
- Protein synthesis inhibition assays, minimal inhibitory concentration (MIC) determination, and cell viability assays.
Main Results:
- Successfully synthesized novel antibiotic compounds via multi-component in situ click reactions.
- Correlated triazole formation with ribosome affinity (Kd values) and identified key interactions.
- Demonstrated potent antibacterial activity and favorable therapeutic indices for synthesized analogues, comparable to solithromycin.
Conclusions:
- The ribosome-templated in situ click chemistry method is effective for discovering and prioritizing potent antibacterial agents.
- This approach enables rapid expansion of chemical diversity for ribosome-targeting antibiotics.
- Identified promising antibiotic candidates with low cytotoxicity for further development.
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