A genetics-free method for high-throughput discovery of cryptic microbial metabolites

Area of Science:

• Microbiology and Natural Products Chemistry

Background:

• Bacteria harbor numerous silent biosynthetic gene clusters (BGCs) containing novel secondary metabolites.
• These BGCs are often not expressed under standard laboratory conditions, limiting the discovery of new bioactive compounds.

Purpose of the Study:

• To develop a universal, high-throughput method for activating silent BGCs in diverse microorganisms.
• To enable the discovery of previously inaccessible microbial metabolites.

Main Methods:

• Elicitor screening was employed to induce secondary metabolite production in various bacterial strains.
• Imaging mass spectrometry was used to visualize and analyze the metabolomes under approximately 500 different conditions.
• The method avoids complex genetic manipulation, cloning, or culturing, making it applicable to both sequenced and unsequenced bacteria.

Main Results:

• The high-throughput method successfully activated silent BGCs across diverse bacterial species.
• Nine cryptic metabolites with potential therapeutic bioactivities were discovered.
• A novel glycopeptide chemotype exhibiting potent inhibitory activity against a pathogenic virus was identified.

Conclusions:

• This universal method provides a powerful tool for unlocking the chemical diversity of bacteria.
• It significantly expands the potential for discovering novel bioactive compounds, including those with antiviral properties.