A macromolecular approach to eradicate multidrug resistant bacterial infections while mitigating drug resistance onset.
Willy ChinGuansheng ZhongQinqin PuChuan YangWeiyang LouPaola Florez De SessionsBalamurugan PeriaswamyAshlynn LeeZhen Chang LiangXin DingShujun GaoCollins Wenhan ChuSimone BiancoChang BaoYen Wah TongWeimin FanXue-Jie YuJames L HedrickYi Yan YangPublished in: Nature communications (2018)
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.
Keyphrases
- multidrug resistant
- drug resistant
- gram negative
- acinetobacter baumannii
- klebsiella pneumoniae
- staphylococcus aureus
- drug delivery
- emergency department
- mouse model
- risk assessment
- high glucose
- endothelial cells
- oxidative stress
- ultrasound guided
- rna seq
- cystic fibrosis
- diabetic rats
- methicillin resistant staphylococcus aureus
- lactic acid
- human health