Identification of the lydiamycin biosynthetic gene cluster in a plant pathogen guides structural revision and identification of molecular target

• DOI: 10.1073/pnas.2424388122
• Publication Date: 2025-05-19T19:07:52Z
• Authors: Jonathan J. Ford; Javier Santos-Abe...; Edward S. Hems; Joseph W. Sallmen; Lena A. K. Bögeholz; Guy Polturak; Anne Osbourn; Joseph A. Wright; Marina V. Rodnina; Danny Vereecke; Isolde M. Francis; Andrew W. Truman
• Keywords: Gene cluster; Natural product; Pentapeptide repeat

The natural products actinonin and matlystatin feature an N -hydroxy-2-pentyl-succinamyl (HPS) chemophore that facilitates metal chelation confers their metalloproteinase inhibitory activity. Actinonin is the most potent inhibitor of peptide deformylase (PDF) exerts antimicrobial herbicidal bioactivity by disrupting protein synthesis. Here, we used a genomics-led approach to identify candidate biosynthetic gene clusters (BGCs) hypothesized produce HPS-containing products. We show one these BGCs on pathogenicity megaplasmid plant pathogen Rhodococcus fascians produces lydiamycin A, macrocyclic pentapeptide. presence genes predicted make HPS-like informed structural recharacterization via NMR crystallography it features rare 2-pentyl-succinyl chemophore. demonstrate A inhibits bacterial PDF in vitro cluster-situated resistance representing uncommon self-immunity mechanism associated with production . In planta competition assays showed enhances fitness R. during colonization. This study highlights how BGC can inform structure, biochemical target, ecological function product.