Housseini B Issa Karim, Phan Gilles, Broutin Isabelle
Laboratoire de Cristallographie et RMN Biologiques (UMR 8015), Centre National de la Recherche Scientifique, Faculté de Pharmacie, Université Paris Descartes, Université Sorbonne Paris Cité, Paris, France.
Front Mol Biosci. 2018 Jun 19;5:57. doi: 10.3389/fmolb.2018.00057. eCollection 2018.
Bacterial antibiotic resistance is a worldwide health problem that deserves important research attention in order to develop new therapeutic strategies. Recently, the World Health Organization (WHO) classified as one of the priority bacteria for which new antibiotics are urgently needed. In this opportunistic pathogen, antibiotics efflux is one of the most prevalent mechanisms where the drug is efficiently expulsed through the cell-wall. This resistance mechanism is highly correlated to the expression level of efflux pumps of the resistance-nodulation-cell division (RND) family, which is finely tuned by gene regulators. Thus, it is worthwhile considering the efflux pump regulators of as promising therapeutical targets alternative. Several families of regulators have been identified, including activators and repressors that control the genetic expression of the pumps in response to an extracellular signal, such as the presence of the antibiotic or other environmental modifications. In this review, based on different crystallographic structures solved from archetypal bacteria, we will first focus on the molecular mechanism of the regulator families involved in the RND efflux pump expression in , which are TetR, LysR, MarR, AraC, and the two-components system (TCS). Finally, the regulators of known structure from will be presented.
细菌抗生素耐药性是一个全球性的健康问题，为了开发新的治疗策略，值得进行重要的研究关注。最近，世界卫生组织（WHO）将其列为迫切需要新抗生素的重点细菌之一。在这种机会性病原体中，抗生素外排是最普遍的机制之一，药物通过细胞壁被有效地排出。这种耐药机制与耐药-结瘤-细胞分裂（RND）家族外排泵的表达水平高度相关，而该家族外排泵的表达水平由基因调控因子精细调节。因此，将外排泵调控因子作为有前景的替代治疗靶点是值得考虑的。已经鉴定出几个调控因子家族，包括响应细胞外信号（如抗生素的存在或其他环境变化）来控制泵的基因表达的激活剂和抑制剂。在本综述中，基于从典型细菌解析出的不同晶体结构，我们将首先关注参与RND外排在其中的调控因子家族的分子机制，这些调控因子家族包括TetR、LysR、MarR、AraC和双组分系统（TCS）。最后，将介绍来自已知结构的调控因子。
