title: Novel Inhibitors of Toxin HipA Reduce Multidrug Tolerant Persisters.
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.
authors.affiliation: Center for Quantitative Biology, Academy for Advanced Interdisciplinary Studies, Peking University , Beijing 100871, China.
authors.forename: Tongqing
authors.initials: T
authors.lastname: Li
authors.affiliation: Center for Quantitative Biology, Academy for Advanced Interdisciplinary Studies, Peking University , Beijing 100871, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Yin
authors.affiliation: Peking-Tsinghua Center for Life Sciences, Peking University , Beijing 100871, China.
authors.forename: Hongbo
authors.initials: H
authors.lastname: Liu
authors.affiliation: Center for Quantitative Biology, Academy for Advanced Interdisciplinary Studies, Peking University , Beijing 100871, China.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Pei
authors.affiliation: 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.
authors.forename: Luhua
authors.initials: L
authors.lastname: Lai
keywords: HipA (high persistence A); Persistence; drug discovery; toxin-antitoxin (TA) module