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Genomic and Spectroscopic Signature-Based Discovery of Natural Macrolactams

Cited 8 time in Web of Science Cited 9 time in Scopus

Shin, Yern-Hyerk; Im, Ji Hyeon; Kang, Ilnam; Kim, Eunji; Jang, Sung Chul; Cho, Eunji; Shin, Daniel; Hwang, Sunghoon; Du, Young Eun; Huynh, Thanh-Hau; Ko, Keebeom; Ko, Yoon-Joo; Nam, Sang-Jip; Awakawa, Takayoshi; Lee, Jeeyeon; Hong, Suckchang; Abe, Ikuro; Moore, Bradley S.; Fenical, William; Yoon, Yeo Joon; Cho, Jang-Cheon; Lee, Sang Kook; Oh, Ki-Bong; Oh, Dong-Chan

Issue Date
American Chemical Society
Journal of the American Chemical Society, Vol.145 No.3, pp.1886-1896
© 2023 American Chemical Society.The logical and effective discovery of macrolactams, structurally unique natural molecules with diverse biological activities, has been limited by a lack of targeted search methods. Herein, a targeted discovery method for natural macrolactams was devised by coupling genomic signature-based PCR screening of a bacterial DNA library with spectroscopic signature-based early identification of macrolactams. DNA library screening facilitated the efficient selection of 43 potential macrolactam-producing strains (3.6% of 1,188 strains screened). The PCR amplicons of the amine-deprotecting enzyme-coding genes were analyzed to predict the macrolactam type (α-methyl, α-alkyl, or β-methyl) produced by the hit strains. 1H-15N HSQC-TOCSY NMR analysis of 15N-labeled culture extracts enabled macrolactam detection and structural type assignment without any purification steps. This method identified a high-titer Micromonospora strain producing salinilactam (1), a previously reported α-methyl macrolactam, and two Streptomyces strains producing new α-alkyl and β-methyl macrolactams. Subsequent purification and spectroscopic analysis led to the structural revision of 1 and the discovery of muanlactam (2), an α-alkyl macrolactam with diene amide and tetraene chromophores, and concolactam (3), a β-methyl macrolactam with a [16,6,6]-tricyclic skeleton. Detailed genomic analysis of the strains producing 1-3 identified putative biosynthetic gene clusters and pathways. Compound 2 displayed significant cytotoxicity against various cancer cell lines (IC50 = 1.58 μM against HCT116), whereas 3 showed inhibitory activity against Staphylococcus aureus sortase A. This genomic and spectroscopic signature-based method provides an efficient search strategy for new natural macrolactams and will be generally applicable for the discovery of nitrogen-bearing natural products.
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Related Researcher

  • College of Pharmacy
  • Department of Manufacturing Pharmacy
Research Area Development of methodologies using metal catalyst, Total synthesis of natural products


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