Targeted Discovery of an Enediyne-Derived Cycloaromatized Compound, Jejucarboside A, from a Marine Actinomycete

Im, Ji Hyeon; Shin, Daniel; Ban, Yeon Hee; Byun, Woong Sub; Bae, Eun Seo; Lee, Dong‐Hoon; Du, Young Eun; Cui, Jinsheng; Kwon, Y.S.; Nam, Sang‐Jip; Cha, Sangwon; Lee, Sang Kook; Yoon, Yeo Joon; Oh, Dong‐Chan

doi:10.1021/acs.orglett.2c02934

Cited by 12 publications

(22 citation statements)

References 26 publications

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“…The absolute configuration of 8 was determined to be identical to 7 by the analysis of circular dichroism (CD) spectroscopic data (Figure S9), thus completing the structure of 8 , termed clavulyne B. In a recent, impressive effort by Oh and colleagues, this metabolite was isolated from 360 L cultures of a marine streptomycete and termed jejucarboside …”

Section: Resultsmentioning

confidence: 86%

“…There is no obvious DNA-targeting moiety or chemical trigger. Clavulynes, therefore, fall in the class of C-1027, maduropeptin, and the precursors of sporolide, cyanosporaside, fijiolide, amycolamycin, and jejucarboside, wherein the position of a triggering system, if any, is not immediately obvious from the structure of the cyclized product. ,, …”

Section: Resultsmentioning

confidence: 99%

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Targeted Discovery of Cryptic Enediyne Natural Products via FRET-Coupled High-Throughput Elicitor Screening

et al. 2023

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Enediyne antibiotics are a striking family of DNAcleaving natural products with high degrees of cytotoxicity and structural complexity. Microbial genome sequences, which have recently accumulated, point to an untapped trove of "cryptic" enediynes. Most of the cognate biosynthetic gene clusters (BGCs) are sparingly expressed under standard growth conditions, making it difficult to characterize their products. Herein, we report a fluorescence-based DNA cleavage assay coupled with highthroughput elicitor screening for the rapid, targeted discovery of cryptic enediyne metabolites. We applied the approach to Streptomyces clavuligerus, which harbors two such BGCs with unknown products, identified steroids as effective elicitors, and characterized 10 cryptic enediyne-derived natural products, termed clavulynes A−J with unusual carbonate and terminal olefin functionalities, with one of these congeners matching the recently reported jejucarboside. Our results contribute to the growing repertoire of enediynes and provide a blueprint for identifying additional ones in the future.

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Section: Resultsmentioning

confidence: 86%

Section: Resultsmentioning

confidence: 99%

Targeted Discovery of Cryptic Enediyne Natural Products via FRET-Coupled High-Throughput Elicitor Screening

et al. 2023

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“…Not every bacterial strain possessing a targeted BGC produces the corresponding compound, that is, some BGCs are silent. Therefore, the unequivocal detection of target compounds in the extracts of the hit strains without purification facilitates the targeted discovery of natural products . The 1 H chemical shifts of 22 macrolactams in DMSO- d 6 and CD 3 OD (Figure and Table S5) were analyzed to develop spectroscopic signatures for α-methyl, α-alkyl, and β-methyl macrolactams and create empirical rules to distinguish these macrolactam types (Table ).…”

Section: Resultsmentioning

confidence: 99%

Genomic and Spectroscopic Signature-Based Discovery of Natural Macrolactams

Shin

Kang

et al. 2023

J. Am. Chem. Soc.

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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. 1 H− 15 N HSQC-TOCSY NMR analysis of 15 Nlabeled 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 (IC 50 = 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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“…[ 9 ]. Our recent genomic and spectroscopic analysis of a marine sand-beach-derived Streptomyces strain resulted in the discovery of a jejucarboside bearing an unusual amino sugar [ 10 ]. Bacillus in marine habitats has also been a chemically prolific bacterial clade since new antiviral and cytotoxic macrolides, macrolactins, were reported from deep-sea Bacillus strain [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

Glycosylated and Succinylated Macrocyclic Lactones with Amyloid-β-Aggregation-Regulating Activity from a Marine Bacillus sp.

Cui

Shin

et al. 2023

Marine Drugs

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Two new glycosylated and succinylated macrocyclic lactones, succinyl glyco-oxydifficidin (1) and succinyl macrolactin O (2), were isolated from a Bacillus strain collected from an intertidal mudflat on Anmyeon Island in Korea. The planar structures of 1 and 2 were proposed using mass spectrometric analysis and NMR spectroscopic data. The absolute configurations of 1 and 2 were determined by optical rotation, J-based configuration analysis, chemical derivatizations, including the modified Mosher’s method, and quantum-mechanics-based calculation. Biological evaluation of 1 and 2 revealed that succinyl glyco-oxydifficidin (1) inhibited/dissociated amyloid β (Aβ) aggregation, whereas succinyl macrolactin O (2) inhibited Aβ aggregation, indicating their therapeutic potential for disassembling and removing Aβ aggregation.

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Targeted Discovery of an Enediyne-Derived Cycloaromatized Compound, Jejucarboside A, from a Marine Actinomycete

Cited by 12 publications

References 26 publications

Targeted Discovery of Cryptic Enediyne Natural Products via FRET-Coupled High-Throughput Elicitor Screening

Targeted Discovery of Cryptic Enediyne Natural Products via FRET-Coupled High-Throughput Elicitor Screening

Genomic and Spectroscopic Signature-Based Discovery of Natural Macrolactams

Glycosylated and Succinylated Macrocyclic Lactones with Amyloid-β-Aggregation-Regulating Activity from a Marine Bacillus sp.

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