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https://doi.org/10.1038/s41467-018-03325-6
Title: | A macromolecular approach to eradicate multidrug resistant bacterial infections while mitigating drug resistance onset | Authors: | Chin, W Zhong, G Pu, Q Yang, C Lou, W De Sessions, P.F Periaswamy, B Lee, A Liang, Z.C Ding, X Gao, S Chu, C.W Bianco, S Bao, C Tong, Y.W Fan, W Wu, M Hedrick, J.L Yang, Y.Y |
Keywords: | guanidine imipenem polycarbonate vancomycin antiinfective agent polymer antibiotics antimicrobial activity bacterial disease biodegradation drug resistance infectious disease microbial activity polymer Acinetobacter baumannii Acinetobacter infection animal cell animal experiment animal model antibacterial activity antibiotic resistance Article bacterial infection bacterial peritonitis controlled study drug efficacy drug therapeutic index ED50 Escherichia coli Escherichia coli infection female IC50 in vitro study in vivo study Klebsiella pneumoniae Klebsiella pneumoniae infection LD50 lung infection macromolecule male methicillin resistant Staphylococcus aureus methicillin resistant Staphylococcus aureus infection minimum inhibitory concentration mouse nonhuman Pseudomonas aeruginosa Pseudomonas infection rat transcriptomics animal bacterial infection bacterium C57BL mouse cecum chemistry disease model drug effects hemolysis Institute for Cancer Research mouse isolation and purification kinetics ligation macromolecule microbial sensitivity test microbiology multidrug resistance pharmacokinetics puncture sequence analysis surgery synthesis therapeutic use tissue distribution Bacteria (microorganisms) Staphylococcus aureus Animals Anti-Infective Agents Bacteria Bacterial Infections Cecum Disease Models, Animal Drug Resistance, Multiple, Bacterial Female Hemolysis Kinetics Ligation Macromolecular Substances Male Mice, Inbred C57BL Mice, Inbred ICR Microbial Sensitivity Tests Polymers Punctures Sequence Analysis, RNA Tissue Distribution |
Issue Date: | 2018 | Publisher: | Nature Publishing Group | Citation: | Chin, W, Zhong, G, Pu, Q, Yang, C, Lou, W, De Sessions, P.F, Periaswamy, B, Lee, A, Liang, Z.C, Ding, X, Gao, S, Chu, C.W, Bianco, S, Bao, C, Tong, Y.W, Fan, W, Wu, M, Hedrick, J.L, Yang, Y.Y (2018). A macromolecular approach to eradicate multidrug resistant bacterial infections while mitigating drug resistance onset. Nature Communications 9 (1) : 917. ScholarBank@NUS Repository. https://doi.org/10.1038/s41467-018-03325-6 | Rights: | Attribution 4.0 International | 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. © 2018 The Author(s). | Source Title: | Nature Communications | URI: | https://scholarbank.nus.edu.sg/handle/10635/178425 | ISSN: | 2041-1723 | DOI: | 10.1038/s41467-018-03325-6 | Rights: | Attribution 4.0 International |
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