Genomic and Spectroscopic Signature-Based Discovery of Natural Macrolactams

Area of Science:

• Natural Product Chemistry
• Genomics
• Microbiology

Background:

• Discovery of macrolactams, natural products with diverse bioactivities, is hindered by a lack of targeted search methods.
• Macrolactams are structurally unique and possess significant therapeutic potential.

Purpose of the Study:

• To develop a targeted discovery method for natural macrolactams by integrating genomic and spectroscopic signatures.
• To identify and characterize novel macrolactams from bacterial sources.

Main Methods:

• Genomic signature-based PCR screening of a bacterial DNA library to identify potential macrolactam-producing strains.
• Spectroscopic signature-based early identification using 1H-15N HSQC-TOCSY NMR for macrolactam detection and structural type assignment.
• Purification and detailed spectroscopic analysis for structural elucidation of new compounds.

Main Results:

• Identified 43 potential macrolactam-producing strains, with 3.6% efficiency.
• Discovered three novel macrolactams: muanlactam (2), an α-alkyl macrolactam, and concolactam (3), a β-methyl macrolactam, alongside a revised structure for salinilactam (1).
• Muanlactam (2) exhibited significant cytotoxicity against cancer cell lines (IC50 = 1.58 μM against HCT116).
• Concolactam (3) demonstrated inhibitory activity against Staphylococcus aureus sortase A.

Conclusions:

• The developed genomic and spectroscopic signature-based method offers an efficient strategy for discovering new natural macrolactams.
• This approach is broadly applicable for the discovery of other nitrogen-bearing natural products.
• The identified novel macrolactams possess promising pharmacological properties for further investigation.