Baena Andres, Vasco Emanuel, Pastrana Manuel, Alzate Juan F, Barrera Luis F, Martínez Alejandro
Grupo de Inmunología Celular e Inmunogenética, Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia.
Grupo de Productos Naturales Marinos, Facultad de Ciencias Farmacéuticas y Alimentarias, Universidad de Antioquia, Medellín, Colombia.
Front Microbiol. 2020 Sep 10;11:537935. doi: 10.3389/fmicb.2020.537935. eCollection 2020.
The upsurge and persistence of drug resistant strains of (Mtb) is an important limitant to the battery of drugs available for the elimination of tuberculosis (TB). To avoid future scarcity of antibiotics against Mtb, it is important to discover new effective anti-mycobacterial agents. In this study, we present data from a series of experiments to determine and anti-mycobacterial activity of a library of epidioxy-sterol analogs. We test 15 compounds for their ability to reduce the viability of Mtb. We found that one compound called T5 epidioxy-sterol-ANB display significant potency against Mtb specifically inside macrophages but without effectivity in axenic cultures. A viability assay confirms that this T5 compound is less toxic for macrophages as compared to the current Mtb drug Rifampicin at higher concentrations. We use a transcriptomic analysis of Mtb inside macrophages after T5 epidioxy-sterol-ANB treatment, and we found a significant down-regulation of enzymes involved in the cholesterol and folic acid pathways. , significant differences were found in the lungs and spleen CFUs of Mtb infected mice treated with the T5 epidioxy-sterol-ANB as compared with the untreated control group, which provides additional evidence of the effectivity of the T5 compound. Altogether these results confirm the potential of this T5 epidioxy-sterol-ANB compound against Mtb.
结核分枝杆菌（Mtb）耐药菌株的激增和持续存在是现有用于消除结核病（TB）的一系列药物的重要限制因素。为避免未来对抗结核分枝杆菌抗生素的短缺，发现新的有效抗分枝杆菌药物很重要。在本研究中，我们展示了一系列实验的数据，以确定表氧化甾醇类似物文库的抗分枝杆菌活性。我们测试了15种化合物降低结核分枝杆菌活力的能力。我们发现一种名为T5表氧化甾醇-ANB的化合物对巨噬细胞内的结核分枝杆菌具有显著效力，但在无菌培养中无效。活力测定证实，与目前的结核分枝杆菌药物利福平相比，这种T5化合物在较高浓度下对巨噬细胞的毒性较小。我们对T5表氧化甾醇-ANB处理后的巨噬细胞内结核分枝杆菌进行了转录组分析，发现参与胆固醇和叶酸途径的酶显著下调。与未处理的对照组相比，在用T5表氧化甾醇-ANB处理的结核分枝杆菌感染小鼠的肺和脾集落形成单位中发现了显著差异，这为T5化合物的有效性提供了额外证据。总之，这些结果证实了这种T5表氧化甾醇-ANB化合物对抗结核分枝杆菌的潜力。
