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Li T, Yin N, Liu H, et al. Novel Inhibitors of Toxin HipA Reduce Multidrug Tolerant Persisters. ACS Med Chem Lett. 2016;7(5):449-53doi: 10.1021/acsmedchemlett.5b00420.
Li, T., Yin, N., Liu, H., Pei, J., & Lai, L. (2016). Novel Inhibitors of Toxin HipA Reduce Multidrug Tolerant Persisters. ACS medicinal chemistry letters, 7(5), 449-53. https://doi.org/10.1021/acsmedchemlett.5b00420
Li, Tongqing, et al. "Novel Inhibitors of Toxin HipA Reduce Multidrug Tolerant Persisters." ACS medicinal chemistry letters vol. 7,5 (2016): 449-53. doi: https://doi.org/10.1021/acsmedchemlett.5b00420
Li T, Yin N, Liu H, Pei J, Lai L. Novel Inhibitors of Toxin HipA Reduce Multidrug Tolerant Persisters. ACS Med Chem Lett. 2016 Mar 13;7(5):449-53. doi: 10.1021/acsmedchemlett.5b00420. eCollection 2016 May 12. PMID: 27190591; PMCID: PMC4867474.
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ACS Med Chem Lett. 2016 Mar 13;7(5):449-53. doi: 10.1021/acsmedchemlett.5b00420. eCollection 2016 May 12.

Novel Inhibitors of Toxin HipA Reduce Multidrug Tolerant Persisters.

ACS medicinal chemistry letters

Tongqing Li, Ning Yin, Hongbo Liu, Jianfeng Pei, Luhua Lai

Affiliations

  1. Center for Quantitative Biology, Academy for Advanced Interdisciplinary Studies, Peking University , Beijing 100871, China.
  2. Peking-Tsinghua Center for Life Sciences, Peking University , Beijing 100871, China.
  3. Center for Quantitative Biology, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China; BNLMS, State Key Laboratory for Structural Chemistry of Unstable and Stable Species, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China; Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China.

PMID: 27190591 PMCID: PMC4867474 DOI: 10.1021/acsmedchemlett.5b00420

Abstract

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.

Keywords: HipA (high persistence A); Persistence; drug discovery; toxin-antitoxin (TA) module

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