Prospecting for natural products by genome mining and microcrystal electron diffraction

Area of Science:

• Biochemistry
• Structural Biology
• Drug Discovery

Background:

• Natural products (NPs) are crucial for pharmaceuticals, but discovery rates have declined.
• Structural characterization is a major bottleneck in identifying new NPs.
• Emerging technologies are needed to overcome limitations in NP discovery.

Purpose of the Study:

• To demonstrate the synergy of microcrystal electron diffraction (MicroED) and genome mining for accelerating natural product discovery and structural elucidation.
• To showcase the application of MicroED in rapidly determining the structures of novel and previously ambiguous natural products.

Main Methods:

• Utilized microcrystal electron diffraction (MicroED), a cryogenic electron microscopy (CryoEM) technique.
• Integrated MicroED with genome mining and synthetic biology approaches.
• Applied the combined methodology to identify and characterize novel 2-pyridone natural products.

Main Results:

• Successfully determined the structure of a new 2-pyridone natural product, designated Py-469.
• Revised and confirmed the structure of fischerin, a cytotoxic NP with previously ambiguous structural assignment.
• Demonstrated the rapid structural elucidation capabilities of the MicroED-based workflow.

Conclusions:

• The combination of MicroED and genome mining significantly accelerates natural product discovery and structural elucidation.
• This integrated approach offers a powerful strategy to overcome bottlenecks in identifying new drug candidates from natural sources.
• The study highlights the potential of MicroED and synthetic biology to revitalize natural product drug discovery efforts.