Target Discovery for New Antitubercular Drugs Using a Large Dataset of Growth Inhibitors from PubChem

Area of Science:

• Microbiology
• Drug Discovery
• Medicinal Chemistry

Background:

• Tuberculosis (TB) treatment is challenged by rising multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains of Mycobacterium tuberculosis.
• Developing new anti-TB drugs is crucial to overcome resistance and shorten treatment durations.

Purpose of the Study:

• To identify novel lead compounds for treating drug-resistant tuberculosis through high-throughput screening.
• To validate identified compounds for efficacy against Mycobacterium tuberculosis and assess their potential drug targets.

Main Methods:

• Conducted a large-scale high-throughput screening (HTS) of 341,778 compounds for Mycobacterium tuberculosis growth inhibition.
• Employed a combined whole-cell screening and target identification approach to ensure cellular activity and address target accessibility.
• Performed rigorous evaluation including reproducibility, potency, medicinal chemistry assessment, and cytotoxicity analysis.

Main Results:

• Identified 8,950 primary hit compounds exhibiting growth inhibitory activity against Mycobacterium tuberculosis.
• Narrowed down to 1,113 priority compounds after comprehensive evaluation.
• Discovered compounds targeting essential bacterial pathways and molecules including Pks13, MmpL3, DprE1, AspS, EthA, GuaB2, and VKOR.

Conclusions:

• The study successfully identified a significant number of novel compounds with potential as anti-TB agents.
• The findings provide valuable resources for further research into drug-resistant TB therapies and target validation.
• Data accessibility through PubChem facilitates collaborative efforts in combating tuberculosis.