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

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A macromolecular approach to eradicate multidrug resistant bacterial infections while mitigating drug resistance onset
Title:
A macromolecular approach to eradicate multidrug resistant bacterial infections while mitigating drug resistance onset
Journal Title:
Nature Communications
Keywords:
Publication Date:
02 March 2018
Citation:
Chin, W., Zhong, G., Pu, Q. et al. A macromolecular approach to eradicate multidrug resistant bacterial infections while mitigating drug resistance onset. Nat Commun 9, 917 (2018).
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.
License type:
http://creativecommons.org/licenses/by/4.0/
Funding Info:
This work was financially supported by the Institute of Bioengineering and Nanotechnology (Biomedical Research Council and ARP-DG 001–005, Agency for Science, Technology and Research, Singapore), and IBM Almaden Research Center (USA). W.C. and Z.C.L. acknowledge the support of National University of Singapore (NUS) Graduate School for Integrative Sciences & Engineering through a Ph.D. Scholarship.
Description:
ISSN:
2041-1723
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