Статья

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

Willy ChinInstitute of Bioengineering and Nanotechnology, 31 Biopolis Way, Singapore, 138669, SingaporeGuansheng ZhongState Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, 310003, ChinaQinqin PuDepartment of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND, 58203, USAChuan YangInstitute of Bioengineering and Nanotechnology, 31 Biopolis Way, Singapore, 138669, SingaporeWeiyang LouState Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, 310003, ChinaPaola Flórez de SessionsGenome Institute of Singapore, 60 Biopolis Street, Genome, Singapore, 138672, SingaporeBalamurugan PeriaswamyGenome Institute of Singapore, 60 Biopolis Street, Genome, Singapore, 138672, SingaporeAshlynn L. Z. LeeInstitute of Bioengineering and Nanotechnology, 31 Biopolis Way, Singapore, 138669, SingaporeZhen LiangInstitute of Bioengineering and Nanotechnology, 31 Biopolis Way, Singapore, 138669, SingaporeXin DingInstitute of Bioengineering and Nanotechnology, 31 Biopolis Way, Singapore, 138669, SingaporeShujun GaoInstitute of Bioengineering and Nanotechnology, 31 Biopolis Way, Singapore, 138669, SingaporeCollins Wenhan ChuGenome Institute of Singapore, 60 Biopolis Street, Genome, Singapore, 138672, SingaporeSimone BiancoIBM Almaden Research Center, 650 Harry Road, San Jose, CA, 95120, USAChang BaoState Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, 310003, ChinaYen Wah TongDepartment of Chemical and Biomolecular Engineering, National University of Singapore, 4 Engineering Drive 4, Singapore, 117576, SingaporeWeimin FanState Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, 310003, ChinaMin WuDepartment of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND, 58203, USA. [email protected]James L. HedrickIBM Almaden Research Center, 650 Harry Road, San Jose, CA, 95120, USA. [email protected]Yi Yan YangInstitute of Bioengineering and Nanotechnology, 31 Biopolis Way, Singapore, 138669, Singapore. [email protected]

2018en

ABI

Аннотация

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—ED 50 /LD 50 : 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.

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Идентификаторы

DOI: 10.1038/s41467-018-03325-6

Цитирования и источники

Цитирований: 2Использованных источников: 0

Показатели — AkademScholar