A Broad Spectrum Lasso Peptide Antibiotic Targeting the Bacterial Ribosome.

Area of Science:

• Microbiology and Molecular Biology
• Natural Product Chemistry
• Antibiotic Discovery

Background:

• Lasso peptides are a class of ribosomally-synthesized and post-translationally modified peptides (RiPPs) with a unique knotted structure and known antibacterial activity.
• While lasso peptides target various bacterial mechanisms, none have been identified as ribosome inhibitors, a key target for antibiotics.

Purpose of the Study:

• To identify and characterize novel lasso peptides with antibacterial properties.
• To investigate the mechanism of action of these new compounds, specifically their effect on bacterial protein synthesis and the ribosome.

Main Methods:

• Isolation and characterization of lariocidin (LAR) and lariocidin B (LAR-B) from *Paenibacillus sp.* M2.
• Biochemical and structural analyses to determine the binding site and interactions with the bacterial ribosome.
• Genetic studies to understand the mechanism of inhibition and assess resistance potential.
• In vivo efficacy testing in a mouse model of *Acinetobacter baumannii* infection.

Main Results:

• Identification of lariocidins (LAR and LAR-B) with broad-spectrum antibacterial activity.
• Demonstration that lariocidins bind to a unique site on the small ribosomal subunit, inhibiting protein synthesis by interfering with translocation and inducing miscoding.
• Lariocidins are effective against pathogens, exhibit low resistance potential, show no human cell toxicity, and are potent in vivo.

Conclusions:

• Lariocidins represent the first class of lasso peptides found to target the bacterial ribosome.
• This discovery opens new avenues for developing alternative protein synthesis inhibitors.
• Lariocidins provide a promising new chemical scaffold for the development of novel antibacterial agents.