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J. Am. Chem. Soc., Aug 29 2023 | https://doi.org/10.1021/jacs.3c04699 Targeted and Logical Discovery of Piperazic Acid-Bearing Natural Products Based on Genomic and Spectroscopic Signatures.

Daniel Shin ¹, Woong Sub Byun ¹, Sangwook Kang ¹, Ilnam Kang ², Eun Seo Bae¹, Joon Soo An ¹, Ji Hyeon Im ¹, Jiyoon Park ¹, Eunji Kim ¹, Keebeom Ko¹, Sunghoon Hwang ¹, Honghui Lee ³, Yun Kwon ⁴, Yoon-Joo Ko ⁵, Suckchang Hong³, Sang-Jip Nam ⁶, Seung Bum Kim ⁷, William Fenical ⁸, Yeo Joon Yoon ^1,9, Jang-Cheon Cho ², Sang Kook Lee¹, Dong-Chan Oh ¹

¹Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.

²Department of Biological Sciences, Inha University, Incheon 22212, Republic of Korea.

³Natural Products Research Institute and Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.

⁴Research Institute of Pharmaceutical Science, College of Pharmacy, Kyungpook National University, Daegu 41566, Republic of Korea.

⁵Laboratory of Nuclear Magnetic Resonance, National Center for Inter-University Research Facilities (NCIRF), Seoul National University, Seoul 08826, Republic of Korea.

⁶Department of Chemistry and Nanoscience, Ewha Womans University, Seoul 03760, Republic of Korea.

⁷Department of Microbiology and Molecular Biology, College of Bioscience and Biotechnology, Chungnam National University, Daejeon 34134, Republic of Korea.

⁸Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography and Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California 92093, United States.

⁹MolGenBio Co., Ltd., Seoul 08826, Republic of Korea.

D.S., W.S.B., and S.K. contributed equally to this work. All authors have given approval to the final version of the manuscript.

Corresponding Authors : Sang Kook Lee, Dong-Chan Oh

Abstract

A targeted and logical discovery method was devised for natural products containing piperazic acid (Piz), which is biosynthesized from ornithine by l-ornithine N-hydroxylase (KtzI) and N- N bond formation enzyme (KtzT). Genomic signature-based screening of a bacterial DNA library (2020 strains) using polymerase chain reaction (PCR) primers targeting ktzT identified 62 strains (3.1%). The PCR amplicons of KtzT-encoding genes were phylogenetically analyzed to classify the 23 clades into two monophyletic groups, I and II. Cultivating hit strains in media supplemented with ¹⁵NH ₄Cl and applying ¹H- ¹⁵N heteronuclear multiple bond correlation (HMBC) along with ¹H- ¹⁵N heteronuclear single quantum coherence (HSQC) and ¹H- ¹⁵N HSQC-total correlation spectroscopy (HSQC-TOCSY) NMR experiments detected the spectroscopic signatures of Piz and modified Piz. Chemical investigation of the hit strains prioritized by genomic and spectroscopic signatures led to the identification of a new azinothricin congener, polyoxyperuin B seco acid ( 1), previously reported chloptosin ( 2) in group I, depsidomycin D ( 3) incorporating two dehydropiperazic acids (Dpz), and lenziamides A and B ( 4 and 5), structurally novel 31-membered cyclic decapeptides in group II. By consolidating the phylogenetic and chemical analyses, clade-structure relationships were elucidated for 19 of the 23 clades. Lenziamide A ( 4) inhibited STAT3 activation and induced G ₂/M cell cycle arrest, apoptotic cell death, and tumor growth suppression in human colorectal cancer cells. Moreover, lenziamide A ( 4) resensitized 5-fluorouracil (5-FU) activity in both in vitro cell cultures and the in vivo 5-FU-resistant tumor xenograft mouse model. This work demonstrates that the genomic and spectroscopic signature-based searches provide an efficient and general strategy for new bioactive natural products containing specific structural motifs.

논문정보

형식Research article
게재일2023년 08월 (BRIC 등록일 2023-09-08)
연구진국내(교신)+국외 연구진
분야 의약학 > 약학

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