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A macromolecular approach to eradicate multidrug resistant bacterial infections while mitigating drug resistance onset

Author

Listed:
  • Willy Chin

    (Institute of Bioengineering and Nanotechnology
    NUS Graduate School for Integrative Sciences and Engineering (NGS))

  • Guansheng Zhong

    (Zhejiang University)

  • Qinqin Pu

    (University of North Dakota)

  • Chuan Yang

    (Institute of Bioengineering and Nanotechnology)

  • Weiyang Lou

    (Zhejiang University)

  • Paola Florez De Sessions

    (Genome Institute of Singapore)

  • Balamurugan Periaswamy

    (Genome Institute of Singapore)

  • Ashlynn Lee

    (Institute of Bioengineering and Nanotechnology)

  • Zhen Chang Liang

    (Institute of Bioengineering and Nanotechnology)

  • Xin Ding

    (Institute of Bioengineering and Nanotechnology)

  • Shujun Gao

    (Institute of Bioengineering and Nanotechnology)

  • Collins Wenhan Chu

    (Genome Institute of Singapore)

  • Simone Bianco

    (IBM Almaden Research Center)

  • Chang Bao

    (Zhejiang University)

  • Yen Wah Tong

    (National University of Singapore)

  • Weimin Fan

    (Zhejiang University)

  • Min Wu

    (University of North Dakota)

  • James L. Hedrick

    (IBM Almaden Research Center)

  • Yi Yan Yang

    (Institute of Bioengineering and Nanotechnology)

Abstract

Polymyxins remain the last line treatment for multidrug-resistant (MDR) infections. As polymyxins resistance emerges, there is an urgent need to develop effective antimicrobial agents capable of mitigating MDR. Here, we report biodegradable guanidinium-functionalized polycarbonates with a distinctive mechanism that does not induce drug resistance. Unlike conventional antibiotics, repeated use of the polymers does not lead to drug resistance. Transcriptomic analysis of bacteria further supports development of resistance to antibiotics but not to the macromolecules after 30 treatments. Importantly, high in vivo treatment efficacy of the macromolecules is achieved in MDR A. baumannii-, E. coli-, K. pneumoniae-, methicillin-resistant S. aureus-, cecal ligation and puncture-induced polymicrobial peritonitis, and P. aeruginosa lung infection mouse models while remaining non-toxic (e.g., therapeutic index—ED50/LD50: 1473 for A. baumannii infection). These biodegradable synthetic macromolecules have been demonstrated to have broad spectrum in vivo antimicrobial activity, and have excellent potential as systemic antimicrobials against MDR infections.

Suggested Citation

  • Willy Chin & Guansheng Zhong & Qinqin Pu & Chuan Yang & Weiyang Lou & Paola Florez De Sessions & Balamurugan Periaswamy & Ashlynn Lee & Zhen Chang Liang & Xin Ding & Shujun Gao & Collins Wenhan Chu & , 2018. "A macromolecular approach to eradicate multidrug resistant bacterial infections while mitigating drug resistance onset," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-03325-6
    DOI: 10.1038/s41467-018-03325-6
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    Cited by:

    1. Tianyu Wu & Min Zhou & Jingcheng Zou & Qi Chen & Feng Qian & Jürgen Kurths & Runhui Liu & Yang Tang, 2024. "AI-guided few-shot inverse design of HDP-mimicking polymers against drug-resistant bacteria," Nature Communications, Nature, vol. 15(1), pages 1-22, December.
    2. Chong Hui Koh & Mallikharjuna Rao Lambu & Chongyun Tan & Guangmin Wei & Zhi Yuan Kok & Kaixi Zhang & Quang Huy Nhat Vu & Muthuvel Panneerselvam & Ying Jie Ooi & Shiow Han Tan & Zheng Wang & Madhu Babu, 2025. "Carbene formation as a mechanism for efficient intracellular uptake of cationic antimicrobial carbon acid polymers," Nature Communications, Nature, vol. 16(1), pages 1-18, December.
    3. Xiaofei Xu & Chiranjeevi Korupalli & Divyanshu Mahajan & Chongyun Tan & Quang Huy Nhat Vu & Loi Thang Pham & Lei Lu & E. Peter Greenberg & Tram T. Dang & Mary B. Chan-Park, 2025. "Poly(imidazolium ester) antibiotic forms intracellular polymer-nucleic acid biomolecular condensates and fight drug-resistant bacteria," Nature Communications, Nature, vol. 16(1), pages 1-17, December.

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