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Figure 1. Discovery timeline of repurposed drugs.
(Figure omitted. See article PDF.)
In the last 3 years, over 16,000 peer-reviewed scientific articles pertaining to tuberculosis (TB) research have been published. This number is likely to continue to increase, as the threat of tuberculosis and the emergence of drug resistant strains continues to pose threats to global health. Discovering the means to prevent and eradicate this disease will be at the forefront of many research agendas. There has been resurgence in interest in applied and translational research for vaccines, diagnostics and drugs to combat TB. However, progress has been slower than anticipated and there remains an urgent need for increased resources and investment into these research areas.
The basic problems
There are numerous technical challenges in identifying suitable antitubercular agents. The extremely slow growth rate of Mycobacterium tuberculosis (mean generation time of 24 h) poses a significant, yet inherent challenge, as this determines the rate of progress of discovery research. In addition, M. tuberculosis is a respiratory pathogen, which has to be handled under strict safety conditions (Biosafety Level 3 in the USA) requiring expensive specialist facilities. The cell wall of M. tuberculosis is waxy, making it a barrier that prevents many small molecules from penetrating into the bacteria and thus unable to access the intended target(s). To make matters worse, M. tuberculosis has efflux pumps that have been implicated in resistance to antibiotics [1]. During infection, the bacteria are found in diverse microenvironments, as well as in replicating and nonreplicating states, requiring drugs to be active under several conditions and against multiple physiologically different states. Given the extended therapy required to treat TB, drugs also need to be safe over long periods of time, without significant side effects or drug-drug interactions.
In order to overcome these issues, researchers have turned to a variety of screening methods to identify promising compound series for development. This review will discuss the current state of TB drug discovery research with particular regard to screening campaigns. In addition, we will explore the methods by which drug targets are being identified and/or validated. Lastly, we will provide our thoughts on the future of TB research and drug discovery, as the improved treatment of tuberculosis is of upmost importance. This is...