Tuberculosis drug discovery in the post-post-genomic era

Area of Science:

• Genomics and infectious disease therapeutics
• Mycobacterium tuberculosis drug discovery

Background:

• Genomics initially promised new infectious disease therapies, but this potential remains largely unrealized.
• Tuberculosis (TB) drug discovery faced challenges with target-based approaches post-genomic era.

Purpose of the Study:

• To review TB drug discovery efforts, particularly those leveraging genomics.
• To discuss the evolution of screening strategies and identification of novel drug candidates.

Main Methods:

• Genomics, including whole genome resequencing, to identify resistance mutations and drug targets.
• Whole cell screening as a primary discovery approach.
• Advanced screening technologies: high-content screening, latency inhibitors, conditional knock-down mutants, and siRNA screens.

Main Results:

• Genomics facilitated the identification of new TB drug candidates through whole cell screening.
• Discovery of 'promiscuous' targets inhibited by diverse compounds.
• Exploration of immunomodulation and host-directed therapies.

Conclusions:

• Genomics has been instrumental in reviving TB drug discovery, albeit through a return to whole cell screening.
• The identification of promiscuous targets presents both challenges and opportunities for drug development.
• Future therapeutic strategies involve advanced screening and host-targeted approaches to combat TB.