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

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, Simone Bianco, Chang Bao, Yen Wah Tong, Weimin Fan, Min Wu (), James L. Hedrick () and Yi Yan Yang ()
Additional contact information
Willy Chin: Institute of Bioengineering and Nanotechnology
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

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-03325-6

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