Univ. Lille, Inserm, Institut Pasteur de Lille, U1177 - Drugs and Molecules for living Systems, F-59000 Lille, France.
Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR9017 - CIIL - Center for Infection and Immunity of Lille, F-59000 Lille, France.
Sci Transl Med. 2022 May 4;14(643):eaaz6280. doi: 10.1126/scitranslmed.aaz6280.
The sensitivity of , the pathogen that causes tuberculosis (TB), to antibiotic prodrugs is dependent on the efficacy of the activation process that transforms the prodrugs into their active antibacterial moieties. Various oxidases of have the potential to activate the prodrug ethionamide. Here, we used medicinal chemistry coupled with a phenotypic assay to select the N-acylated 4-phenylpiperidine compound series. The lead compound, SMARt751, interacted with the transcriptional regulator VirS of , which regulates the operon encoding a monooxygenase that activates ethionamide. SMARt751 boosted the efficacy of ethionamide in vitro and in mouse models of acute and chronic TB. SMARt751 also restored full efficacy of ethionamide in mice infected with strains carrying mutations in the gene, which cause ethionamide resistance in the clinic. SMARt751 was shown to be safe in tests conducted in vitro and in vivo. A model extrapolating animal pharmacokinetic and pharmacodynamic parameters to humans predicted that as little as 25 mg of SMARt751 daily would allow a fourfold reduction in the dose of ethionamide administered while retaining the same efficacy and reducing side effects.
导致结核病（TB）的病原体 对抗生素前药的敏感性取决于将前药转化为其活性抗菌部分的激活过程的功效。 具有将前药乙硫异烟胺转化为其活性形式的潜在能力。 在这里，我们使用药物化学结合表型测定法来选择 N-酰化 4-苯基哌啶化合物系列。 先导化合物 SMARt751 与转录调节剂 VirS 相互作用，该调节剂调节编码单加氧酶的 操纵子，该酶激活乙硫异烟胺。 SMARt751 提高了乙硫异烟胺在体外和急性和慢性 TB 小鼠模型中的功效。 SMARt751 还恢复了携带 基因中突变的 菌株感染的小鼠中乙硫异烟胺的全部功效，该突变导致临床上乙硫异烟胺耐药。 SMARt751 在体外和体内试验中均显示安全。 一种将动物药代动力学和药效学参数外推至人类的模型预测，每天仅需 25 毫克 SMARt751 就可以将乙硫异烟胺的剂量减少四倍，而保持相同的功效并减少副作用。
