Genomic and Spectroscopic Signature-Based Discovery of Natural Macrolactams.
Journal of the American Chemical Society(2023)
摘要
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. H-N HSQC-TOCSY NMR analysis of N-labeled culture extracts enabled macrolactam detection and structural type assignment without any purification steps. This method identified a high-titer strain producing salinilactam (), a previously reported α-methyl macrolactam, and two strains producing new α-alkyl and β-methyl macrolactams. Subsequent purification and spectroscopic analysis led to the structural revision of and the discovery of muanlactam (), an α-alkyl macrolactam with diene amide and tetraene chromophores, and concolactam (), a β-methyl macrolactam with a [16,6,6]-tricyclic skeleton. Detailed genomic analysis of the strains producing - identified putative biosynthetic gene clusters and pathways. Compound displayed significant cytotoxicity against various cancer cell lines (IC = 1.58 μM against HCT116), whereas showed inhibitory activity against 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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关键词
spectroscopic,signature-based
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