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Evolution-guided discovery of antibiotics that inhibit peptidoglycan remodelling

Author

Listed:
  • Elizabeth J. Culp

    (McMaster University)

  • Nicholas Waglechner

    (McMaster University)

  • Wenliang Wang

    (McMaster University)

  • Aline A. Fiebig-Comyn

    (McMaster University)

  • Yen-Pang Hsu

    (Indiana University)

  • Kalinka Koteva

    (McMaster University)

  • David Sychantha

    (McMaster University)

  • Brian K. Coombes

    (McMaster University)

  • Michael S. Nieuwenhze

    (Indiana University)

  • Yves V. Brun

    (Indiana University
    Université de Montréal, Montreal)

  • Gerard D. Wright

    (McMaster University)

Abstract

Addressing the ongoing antibiotic crisis requires the discovery of compounds with novel mechanisms of action that are capable of treating drug-resistant infections1. Many antibiotics are sourced from specialized metabolites produced by bacteria, particularly those of the Actinomycetes family2. Although actinomycete extracts have traditionally been screened using activity-based platforms, this approach has become unfavourable owing to the frequent rediscovery of known compounds. Genome sequencing of actinomycetes reveals an untapped reservoir of biosynthetic gene clusters, but prioritization is required to predict which gene clusters may yield promising new chemical matter2. Here we make use of the phylogeny of biosynthetic genes along with the lack of known resistance determinants to predict divergent members of the glycopeptide family of antibiotics that are likely to possess new biological activities. Using these predictions, we uncovered two members of a new functional class of glycopeptide antibiotics—the known glycopeptide antibiotic complestatin and a newly discovered compound we call corbomycin—that have a novel mode of action. We show that by binding to peptidoglycan, complestatin and corbomycin block the action of autolysins—essential peptidoglycan hydrolases that are required for remodelling of the cell wall during growth. Corbomycin and complestatin have low levels of resistance development and are effective in reducing bacterial burden in a mouse model of skin MRSA infection.

Suggested Citation

  • 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.
  • Handle: RePEc:nat:nature:v:578:y:2020:i:7796:d:10.1038_s41586-020-1990-9
    DOI: 10.1038/s41586-020-1990-9
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    Cited by:

    1. 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.
    2. 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.
    3. 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.
    4. 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.
    5. 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.
    6. 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.
    7. 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.
    8. 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.

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