IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v12y2021i1d10.1038_s41467-021-27404-3.html
   My bibliography  Save this article

Reductive inactivation of the hemiaminal pharmacophore for resistance against tetrahydroisoquinoline antibiotics

Author

Listed:
  • Wan-Hong Wen

    (University of Chinese Academy of Sciences, Chinese Academy of Sciences)

  • Yue Zhang

    (University of Chinese Academy of Sciences, Chinese Academy of Sciences)

  • Ying-Ying Zhang

    (University of Chinese Academy of Sciences, Chinese Academy of Sciences)

  • Qian Yu

    (Shanghai Jiao Tong University)

  • Chu-Chu Jiang

    (Shanghai Jiao Tong University)

  • Man-Cheng Tang

    (University of Chinese Academy of Sciences, Chinese Academy of Sciences)

  • Jin-Yue Pu

    (University of Chinese Academy of Sciences, Chinese Academy of Sciences)

  • Lian Wu

    (University of Chinese Academy of Sciences, Chinese Academy of Sciences)

  • Yi-Lei Zhao

    (Shanghai Jiao Tong University)

  • Ting Shi

    (Shanghai Jiao Tong University)

  • Jiahai Zhou

    (Chinese Academy of Sciences)

  • Gong-Li Tang

    (University of Chinese Academy of Sciences, Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

Abstract

Antibiotic resistance is becoming one of the major crises, among which hydrolysis reaction is widely employed by bacteria to destroy the reactive pharmacophore. Correspondingly, antibiotic producer has canonically co-evolved this approach with the biosynthetic capability for self-resistance. Here we discover a self-defense strategy featuring with reductive inactivation of hemiaminal pharmacophore by short-chain dehydrogenases/reductases (SDRs) NapW and homW, which are integrated with the naphthyridinomycin biosynthetic pathway. We determine the crystal structure of NapW·NADPH complex and propose a catalytic mechanism by molecular dynamics simulation analysis. Additionally, a similar detoxification strategy is identified in the biosynthesis of saframycin A, another member of tetrahydroisoquinoline (THIQ) antibiotics. Remarkably, similar SDRs are widely spread in bacteria and able to inactive other THIQ members including the clinical anticancer drug, ET-743. These findings not only fill in the missing intracellular events of temporal-spatial shielding mode for cryptic self-resistance during THIQs biosynthesis, but also exhibit a sophisticated damage-control in secondary metabolism and general immunity toward this family of antibiotics.

Suggested Citation

  • Wan-Hong Wen & Yue Zhang & Ying-Ying Zhang & Qian Yu & Chu-Chu Jiang & Man-Cheng Tang & Jin-Yue Pu & Lian Wu & Yi-Lei Zhao & Ting Shi & Jiahai Zhou & Gong-Li Tang, 2021. "Reductive inactivation of the hemiaminal pharmacophore for resistance against tetrahydroisoquinoline antibiotics," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
  • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-27404-3
    DOI: 10.1038/s41467-021-27404-3
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-021-27404-3
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-021-27404-3?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Hua Yuan & Jinru Zhang & Yujuan Cai & Sheng Wu & Kui Yang & H. C. Stephen Chan & Wei Huang & Wen-Bing Jin & Yan Li & Yue Yin & Yasuhiro Igarashi & Shuguang Yuan & Jiahai Zhou & Gong-Li Tang, 2017. "GyrI-like proteins catalyze cyclopropanoid hydrolysis to confer cellular protection," Nature Communications, Nature, vol. 8(1), pages 1-8, December.
    2. Elizabeth J. Culp & Nicholas Waglechner & Wenliang Wang & Aline A. Fiebig-Comyn & Yen-Pang Hsu & Kalinka Koteva & David Sychantha & Brian K. Coombes & Michael S. Nieuwenhze & Yves V. Brun & Gerard D. , 2020. "Evolution-guided discovery of antibiotics that inhibit peptidoglycan remodelling," Nature, Nature, vol. 578(7796), pages 582-587, February.
    3. Lida Rostock & Ronja Driller & Stefan Grätz & Dennis Kerwat & Leonard Eckardstein & Daniel Petras & Maria Kunert & Claudia Alings & Franz-Josef Schmitt & Thomas Friedrich & Markus C. Wahl & Bernhard L, 2018. "Molecular insights into antibiotic resistance - how a binding protein traps albicidin," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Mathias H. Hansen & Martina Adamek & Dumitrita Iftime & Daniel Petras & Frauke Schuseil & Stephanie Grond & Evi Stegmann & Max J. Cryle & Nadine Ziemert, 2023. "Resurrecting ancestral antibiotics: unveiling the origins of modern lipid II targeting glycopeptides," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    2. Christopher J. Barden & Fan Wu & J. Pedro Fernandez-Murray & Erhu Lu & Shengguo Sun & Marcia M. Taylor & Annette L. Rushton & Jason Williams & Mahtab Tavasoli & Autumn Meek & Alla Siva Reddy & Lisa M., 2024. "Computer-aided drug design to generate a unique antibiotic family," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    3. Zhuo Cheng & Bei-Bei He & Kangfan Lei & Ying Gao & Yuqi Shi & Zheng Zhong & Hongyan Liu & Runze Liu & Haili Zhang & Song Wu & Wenxuan Zhang & Xiaoyu Tang & Yong-Xin Li, 2024. "Rule-based omics mining reveals antimicrobial macrocyclic peptides against drug-resistant clinical isolates," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    4. Xueqin Shu & Yingying Shi & Yi Huang & Dan Yu & Baolin Sun, 2023. "Transcription tuned by S-nitrosylation underlies a mechanism for Staphylococcus aureus to circumvent vancomycin killing," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    5. Qian Li & Shang Chen & Kui Zhu & Xiaoluo Huang & Yucheng Huang & Zhangqi Shen & Shuangyang Ding & Danxia Gu & Qiwen Yang & Hongli Sun & Fupin Hu & Hui Wang & Jiachang Cai & Bing Ma & Rong Zhang & Jian, 2022. "Collateral sensitivity to pleuromutilins in vancomycin-resistant Enterococcus faecium," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    6. Andrew M. King & Daniel A. Anderson & Emerson Glassey & Thomas H. Segall-Shapiro & Zhengan Zhang & David L. Niquille & Amanda C. Embree & Katelin Pratt & Thomas L. Williams & D. Benjamin Gordon & Chri, 2021. "Selection for constrained peptides that bind to a single target protein," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    7. Elwood A. Mullins & Jonathan Dorival & Gong-Li Tang & Dale L. Boger & Brandt F. Eichman, 2021. "Structural evolution of a DNA repair self-resistance mechanism targeting genotoxic secondary metabolites," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    8. Laura Nies & Susheel Bhanu Busi & Mina Tsenkova & Rashi Halder & Elisabeth Letellier & Paul Wilmes, 2022. "Evolution of the murine gut resistome following broad-spectrum antibiotic treatment," Nature Communications, Nature, vol. 13(1), pages 1-11, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-27404-3. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.