Molecular Networking‐Guided Discovery of Kyonggic Acids in Massilia spp

• Published in: European journal of organic chemistry 2024-05, Vol.27 (17), p.n/a
• Main Authors: Steinmetz, Till, Lindig, Anton, Lütz, Stephan, Nett, Markus
• Format: Article
• Language: English
• Subjects: Amino acids; Annotations; Bacteria; Biological activity; Biosynthesis; Mass spectrometry; Massilia; Metabolites; metabolome; molecular network; N-acyl amino acid; Natural products; Software; structure elucidation; Tyrosinase
• ISSN: 1434-193X; 1099-0690
• DOI: 10.1002/ejoc.202400017

In recent years, bacteria of the genus Massilia have been identified as promising sources of bioactive natural products. In this study, we used mass spectrometry (MS)‐based molecular networking for the first comprehensive analysis of the secondary metabolome of these microorganisms. Annotation of the detected metabolite clusters with a mass fragmentation database revealed several compounds not previously known to be produced by Massilia species. To secure sufficient material for further structural analyses as well as biological testing, we selected the most promising producer strains from our molecular networking analysis and subjected them to larger‐scale cultivation. Following extraction and UV‐directed isolation, we obtained five metabolites in milligram quantities. In addition to a cyclic dipeptide, we elucidated the structures of four acyl amino acids that are related to thalassotalic acid C from the marine bacterium Thalassotalea sp. The Massilia‐derived kyonggic acids were found to inhibit the enzyme tyrosinase, which is involved in melanin biosynthesis influencing skin and hair pigmentation. This study illustrates the value of combining spectroscopic and computational tools in natural product discovery in order to detect and guide the isolation of previously overlooked bioactive compounds. The metabolomes of six Massilia strains were analyzed using a molecular‐networking guided approach, revealing interconnections among metabolites. A closer inspection of the most promising strains led to the discovery of novel N‐acylated amino acids, termed kyonggic acids. Additionally, cluster analysis also unveiled previously described metabolites such as massiliachelin and its biosynthetic shunt products.