A family of lanthipeptides with anti-phage function

Area of Science:

• Microbiology
• Natural Product Chemistry
• Bacteriophage Biology

Background:

• Bacterial natural products are crucial for environmental adaptation, with phage interactions being key drivers.
• While some natural products offer protection against phages, the chemical diversity of anti-phage defenses is not well understood.

Purpose of the Study:

• To identify and characterize novel bacterial anti-phage defense mechanisms.
• To explore the potential of lanthipeptide biosynthetic gene clusters (BGCs) as a source of anti-phage compounds.

Main Methods:

• Bioinformatic identification of lanthipeptide BGCs in Actinobacteria.
• Demonstration of anti-phage activity in native and heterologous expression systems.
• Mutational analysis of lanthivirin biosynthetic machinery and core peptide.
• Genetic and biochemical assays during phage infection.

Main Results:

• Identified a widespread family of lanthipeptide BGCs, termed lanthivirins, conferring anti-phage activity.
• Lanthivirin BGCs are often found in genomic defense islands, co-localizing with other defense systems.
• Lanthivirin maturation is essential for anti-phage activity, which involves phage-protein-dependent inhibition of phage DNA replication.
• No host toxicity was observed.

Conclusions:

• Lanthivirins represent a novel class of bacterial anti-phage natural products.
• BGCs are a promising resource for discovering new antiviral compounds.
• Lanthivirins offer a phage-protein-dependent mechanism for inhibiting phage DNA replication without host toxicity.