Structure-based design of DevR inhibitor active against nonreplicating Mycobacterium tuberculosis

Area of Science:

• Microbiology
• Drug Discovery
• Molecular Biology

Background:

• Current antitubercular treatments primarily target actively replicating Mycobacterium tuberculosis.
• Persistent, dormant subpopulations of M. tuberculosis pose a significant challenge for effective treatment.
• The DevR response regulator is crucial for bacterial adaptation to dormancy under hypoxic conditions.

Purpose of the Study:

• To identify and characterize novel inhibitors targeting the DevR response regulator.
• To explore DevR as a potential target for developing sterilizing antitubercular agents.

Main Methods:

• Homology modeling was used to create a 3D model of the DevR protein.
• In silico pharmacophore-based screening of a large compound library was performed.
• A phenylcoumarin derivative (compound 10) was identified and further characterized.
• Compound 10's effect on DevR DNA binding, gene transcription, and bacterial survival was assessed.

Main Results:

• Compound 10 was identified as a potent inhibitor of DevR DNA binding.
• Treatment with compound 10 down-regulated the transcription of key dormancy genes.
• Compound 10 significantly reduced the survival of hypoxic dormant bacteria, but not nutrient-starved dormant or actively growing bacteria.
• Compound 10 appears to "lock" DevR in an inactive conformation.

Conclusions:

• DevR is a validated novel target for developing antitubercular drugs.
• Compound 10 demonstrates proof-of-concept for targeting dormant M. tuberculosis with sterilizing activity.
• This study provides a promising avenue for developing new therapies against persistent tuberculosis infections.