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A Macromolecule Reversing Antibiotic Resistance Phenotype and Repurposing Drugs as Potent Antibiotics
Advanced Science ( IF 14.3 ) Pub Date : 2020-07-21 , DOI: 10.1002/advs.202001374
Xin Ding 1, 2 , Chuan Yang 2 , Wilfried Moreira 3 , Peiyan Yuan 1 , Balamurugan Periaswamy 2 , Paola Florez de Sessions 4 , Huimin Zhao 1 , Jeremy Tan 2 , Ashlynn Lee 2 , Kai Xun Ong 3 , Nathaniel Park 5 , Zhen Chang Liang 2 , James L Hedrick 5 , Yi Yan Yang 2
Affiliation  

In order to mitigate antibiotic resistance, a new strategy to increase antibiotic potency and reverse drug resistance is needed. Herein, the translocation mechanism of an antimicrobial guanidinium‐functionalized polycarbonate is leveraged in combination with traditional antibiotics to afford a potent treatment for drug‐resistant bacteria. Particularly, this polymer–antibiotic combination approach reverses rifampicin resistance phenotype in Acinetobacter baumannii demonstrating a 2.5 × 105‐fold reduction in minimum inhibitory concentration (MIC) and a 4096‐fold reduction in minimum bactericidal concentration (MBC). This approach also enables the repurposing of auranofin as an antibiotic against multidrug‐resistant (MDR) Gram‐negative bacteria with a 512‐fold MIC and 128‐fold MBC reduction, respectively. Finally, the in vivo efficacy of polymer–rifampicin combination is demonstrated in a MDR bacteremia mouse model. This combination approach lays foundational ground rules for a new class of antibiotic adjuvants capable of reversing drug resistance phenotype and repurposing drugs against MDR Gram‐negative bacteria.

中文翻译:

逆转抗生素耐药表型的大分子并将药物重新用作有效的抗生素

为了减轻抗生素耐药性,需要一种提高抗生素效力和逆转耐药性的新策略。在此,利用抗菌胍功能化聚碳酸酯的易位机制与传统抗生素相结合,为耐药细菌提供有效的治疗。特别是,这种聚合物-抗生素组合方法逆转了鲍曼不动杆菌中的利福平耐药表型,最低抑菌浓度(MIC)降低了2.5 × 10 5倍,最低杀菌浓度(MBC)降低了 4096 倍。这种方法还可以将金诺芬重新用作针对多重耐药 (MDR) 革兰氏阴性菌的抗生素,其 MIC 降低 512 倍,MBC 降低 128 倍。最后,聚合物-利福平组合的体内功效在 MDR 菌血症小鼠模型中得到证实。这种组合方法为能够逆转耐药表型并重新利用针对多重耐药革兰氏阴性菌的药物的新型抗生素佐剂奠定了基础规则。
更新日期:2020-09-10
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