Mechanism of the M. tuberculosis DprE1-DprE2 epimerase complex and inhibition by anti-tubercular drugs.

Cryo-EM structures reveal how the M. tuberculosis DprE1-DprE2 complex interacts with anti-tubercular drugs, providing insights into their mechanisms of inhibition.

• Why it matters: Understanding the detailed mechanisms of these enzymes and their inhibition is crucial for developing more effective tuberculosis treatments, addressing drug resistance and improving efficacy.
• What they did: Researchers used cryo-electron microscopy to determine structures of the DprE1-DprE2 complex bound to substrates and inhibitors, including pretomanid, delamanid, and quabodepistat, revealing binding modes and complex assembly.
• The result: The findings clarify how these drugs target the complex, enabling rational design of new compounds with enhanced activity against M. tuberculosis.