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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
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    References listed on IDEAS

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    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. 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.
    3. 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.
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