Department of Medical Microbiology and Infection Control, Amsterdam UMC, Location Vrije Universiteit Medical Center, De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands.
Section Molecular Microbiology, Amsterdam Institute of Molecular and Life Sciences, Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands.
Dis Model Mech. 2021 Dec 1;14(12). doi: 10.1242/dmm.049145. Epub 2021 Dec 23.
Finding new anti-tuberculosis compounds with convincing in vivo activity is an ongoing global challenge to fight the emergence of multidrug-resistant Mycobacterium tuberculosis isolates. In this study, we exploited the medium-throughput capabilities of the zebrafish embryo infection model with Mycobacterium marinum as a surrogate for M. tuberculosis. Using a representative set of clinically established drugs, we demonstrate that this model could be predictive and selective for antibiotics that can be administered orally. We further used the zebrafish infection model to screen 240 compounds from an anti-tuberculosis hit library for their in vivo activity and identified 14 highly active compounds. One of the most active compounds was the tetracyclic compound TBA161, which was studied in more detail. Analysis of resistant mutants revealed point mutations in aspS (rv2572c), encoding an aspartyl-tRNA synthetase. The target was genetically confirmed, and molecular docking studies propose the possible binding of TBA161 in a pocket adjacent to the catalytic site. This study shows that the zebrafish infection model is suitable for rapidly identifying promising scaffolds with in vivo activity.
寻找具有令人信服的体内活性的新型抗结核化合物是全球范围内对抗耐多药结核分枝杆菌分离株出现的一项持续挑战。在这项研究中，我们利用斑马鱼胚胎感染模型（以海洋分枝杆菌作为结核分枝杆菌的替代物）的高通量能力。我们使用一组具有代表性的临床确立的药物，证明该模型可用于预测和选择可口服给予的抗生素。我们进一步利用斑马鱼感染模型筛选了 240 种来自抗结核化合物库的化合物，以评估其体内活性，并确定了 14 种具有高度活性的化合物。其中最有效的化合物之一是四环化合物 TBA161，我们对其进行了更详细的研究。抗性突变体分析显示，编码天冬氨酰-tRNA 合成酶的 aspS（rv2572c）发生点突变。该靶标已通过遗传确认，分子对接研究表明 TBA161 可能结合在靠近催化位点的口袋中。这项研究表明，斑马鱼感染模型适合于快速识别具有体内活性的有前途的支架。
