Manjunatha Ujjini H, Smith Paul W
Novartis Institute for Tropical Diseases (NITD), 10 Biopolis Road, Chromos #05-01, Singapore 138670, Singapore.
Bioorg Med Chem. 2015 Aug 15;23(16):5087-97. doi: 10.1016/j.bmc.2014.12.031. Epub 2014 Dec 24.
Tuberculosis poses a major global health problem and multi-drug resistant strains are increasingly prevalent. Hence there is an urgent need to discover new TB drugs. Cell based phenotypic screening represents a powerful approach to identify anti-mycobacterial compounds and elucidate novel targets. Three high throughput phenotypic screens were performed at NITD against mycobacterium. Hits were identified and chemical series selected for optimisation. This produced compounds with good in vitro anti-mycobacterial activity and pharmacokinetic properties. Some compounds displayed oral activity in mouse efficacy models of TB. Herein, we review the TB discovery efforts at NITD and share experiences in optimisation of phenotypic hits, describing challenges encountered and lessons learned. We also offer perspectives to facilitate future selection and advancement of phenotypic hits.
结核病是一个重大的全球健康问题，耐多药菌株日益普遍。因此，迫切需要发现新的抗结核药物。基于细胞的表型筛选是一种识别抗分枝杆菌化合物和阐明新靶点的有效方法。国家热带病研究所针对分枝杆菌进行了三项高通量表型筛选。识别出了活性化合物，并选择了化学系列进行优化。这产生了具有良好体外抗分枝杆菌活性和药代动力学特性的化合物。一些化合物在结核病小鼠疗效模型中显示出口服活性。在此，我们回顾了国家热带病研究所在结核病药物发现方面所做的工作，并分享了表型活性化合物优化方面的经验，描述了遇到的挑战和吸取的教训。我们还提供了一些观点，以促进未来对表型活性化合物的筛选和推进。
