Polymyxins and analogues bind to ribosomal RNA and interfere with eukaryotic translation in vitro

Area of Science:

• Microbiology
• Molecular Biology
• Pharmacology

Background:

• Polymyxins are critical antibiotics for treating infections caused by Gram-negative bacteria.
• Their primary mechanism of action is understood to involve disruption of bacterial membrane integrity.
• However, the full spectrum of polymyxin interactions and their clinical implications remain incompletely understood.

Purpose of the Study:

• To investigate novel molecular targets of polymyxins beyond membrane disruption.
• To explore the potential impact of polymyxins on host cell translational processes.
• To identify mechanisms contributing to polymyxin-associated toxicity.

Main Methods:

• In vitro binding assays to identify antibiotic targets.
• Analysis of interactions with ribosomal A-sites in prokaryotic and eukaryotic systems.
• In vitro translation assays to assess functional effects on protein synthesis.

Main Results:

• Polymyxins, including Polymyxin B and colistin, were found to bind to the A-site of ribosomes in both prokaryotic and eukaryotic cells.
• These antibiotics inhibited eukaryotic translation in vitro.
• The binding to translational machinery represents a newly identified molecular interaction for polymyxins.

Conclusions:

• Polymyxin antibiotics interact with the A-site of ribosomes, a key component of translational decoding.
• This interaction with eukaryotic translation machinery may contribute to the adverse effects observed clinically.
• These findings suggest new avenues for understanding polymyxin pharmacology and toxicity.