Centre for Biodiscovery, Victoria University of Wellington, School of Biological Sciences, PO Box 600, Wellington , New Zealand +64 4 463 6088 ; +64 4 463 5331 ;
Expert Opin Drug Discov. 2011 Aug;6(8):839-54. doi: 10.1517/17460441.2011.586999. Epub 2011 May 25.
Mycobacterium tuberculosis kills more people than any other bacterial pathogen. New drugs are required to shorten the treatment time and provide a viable therapy for drug-resistant and latent forms of tuberculosis. The tuberculosis field has advanced considerably since the publication of the M. tuberculosis genome sequence. Today, researchers can build a high definition map of the pathogen's traits and behavior and select individual targets for chemical disruption.
This review examines the discovery of current clinical and candidate tuberculosis drugs. It outlines recent developments in the selection of molecular targets for the discovery of new anti-mycobacterial agents. It appraises techniques that incorporate target knowledge into the screening protocol. These techniques include in silico, in vitro enzyme-based, differential antisense sensitivity and gene expression screening systems. The review also looks ahead to further techniques that may be applied in tuberculosis drug discovery.
The adoption of an 'either/or' approach to targeted or random tuberculosis drug screening is not expected. The historical success of random screening in providing the tuberculosis drugs currently in clinical use is likely to ensure that non-targeted protocols retain an important role in drug screening. However, a number of M. tuberculosis inhibitors in lead optimization and preclinical development have been discovered using targeted methods. Realization of the first clinically-approved tuberculosis drugs derived from targeted screening and continued refinements in targeted screening technologies are likely to increase the adoption of targeted approaches in the future.
结核分枝杆菌是导致人类死亡人数最多的细菌病原体。为了缩短治疗时间并为耐药和潜伏性结核提供可行的治疗方法，我们需要开发新的药物。自结核分枝杆菌基因组序列公布以来，结核病领域已经取得了相当大的进展。如今，研究人员可以构建病原体特征和行为的高清晰度图谱，并选择单个靶标进行化学破坏。
本文综述了当前临床和候选结核病药物的发现。概述了近年来针对新的抗分枝杆菌药物发现选择分子靶标的最新进展。评估了将靶标知识纳入筛选方案的技术。这些技术包括基于计算机的、基于体外酶的、差异反义敏感性和基因表达筛选系统。本文还展望了可能应用于结核病药物发现的进一步技术。
预计不会采用针对或随机的结核病药物筛选的“非此即彼”方法。随机筛选在提供目前临床使用的结核病药物方面的历史成功，可能确保非靶向方案在药物筛选中仍发挥重要作用。然而，一些处于优化和临床前开发阶段的结核分枝杆菌抑制剂是通过靶向方法发现的。首个基于靶向筛选并经临床批准的结核病药物的问世，以及靶向筛选技术的不断完善，可能会增加未来靶向方法的采用。
