Structural basis for differential inhibition of eukaryotic ribosomes by tigecycline

Area of Science:

• Structural Biology
• Molecular Biology
• Drug Discovery

Background:

• Tigecycline is a crucial antibiotic for complex bacterial infections.
• Its mechanism of inhibiting human cell cytotoxicity is not fully understood.
• Tigecycline targets bacterial protein synthesis by blocking the ribosomal A-site.

Purpose of the Study:

• To elucidate the molecular mechanism of tigecycline's action on human ribosomes.
• To determine the structural basis for tigecycline's cytotoxicity.
• To investigate tigecycline binding to human mitochondrial (55S) and cytoplasmic (80S) ribosomes.

Main Methods:

• Cryo-electron microscopy (cryo-EM) to determine high-resolution structures.
• Analysis of tigecycline binding to human 55S, human 80S, and yeast 80S ribosomes.
• Comparison of binding at clinically relevant and high concentrations.

Main Results:

• Tigecycline binds human 55S mitoribosomes at clinical concentrations, hindering tRNA accommodation and blocking the peptidyl transfer center.
• Tigecycline does not bind human 80S ribosomes at physiological concentrations.
• At high concentrations, tigecycline binds both human and yeast 80S ribosomes at the A-site and an L1 stalk-restricted site.

Conclusions:

• Tigecycline exhibits distinct binding properties to human mitoribosomes and 80S ribosomes.
• These findings provide structural insights into tigecycline's mechanism of action and cytotoxicity.
• The distinct binding modes may inform the development of novel antibiotics and therapeutic strategies.