Novel Inhibitors of Toxin HipA Reduce Multidrug Tolerant Persisters

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• 作者：Tongqing Li ; Ning Yin ; Hongbo Liu ; Jianfeng Pei ; Luhua Lai
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：May 12, 2016
• 年：2016
• 卷：7
• 期：5
• 页码：449-453
• 全文大小：409K
• 年卷期：0
• ISSN：1948-5875

文摘

Persisters are a small fraction of drug-tolerant bacteria without any genotype variations. Their existence in many life-threatening infectious diseases presents a major challenge to antibiotic therapy. Persistence is highly related to toxin–antitoxin modules. HipA (high persistence A) was the first toxin found to contribute to Escherichia coli persistence. In this study, we used structure-based virtual screening for HipA inhibitors discovery and identified several novel inhibitors of HipA that remarkably reduced E. coli persistence. The most potent one decreased the persister fraction by more than five-fold with an in vitro K_D of 270 ± 90 nM and an ex vivo EC₅₀ of 46 ± 2 and 28 ± 1 μM for ampicillin and kanamycin screening, respectively. These findings demonstrated that inhibition of toxin can reduce bacterial persistence independent of the antibiotics used and provided a framework for persistence treatment by interfering with the toxin–antitoxin modules.