DNA Aptamer Targets Mycobacterium tuberculosis DevR/DosR Response Regulator Function by Inhibiting Its Dimerization...

Area of Science:

• Microbiology
• Molecular Biology
• Drug Discovery

Background:

• Tuberculosis remains a significant global health challenge.
• The DevR-DevS two-component system in Mycobacterium tuberculosis (Mtb) is a promising drug target for combating persistent infections.
• Challenges exist in developing anti-DevR drugs due to increased DevR levels and reduced cell wall permeability during dormancy.

Purpose of the Study:

• To develop novel inhibitors targeting the Mtb DevR protein.
• To explore the potential of DNA aptamers as therapeutic agents against intracellular bacterial proteins.

Main Methods:

• Systematic Evolution of Ligands by EXponential enrichment (SELEX) was employed to identify DNA aptamers against Mtb DevR.
• Solid-phase binding assays were used to screen aptamer-protein interactions.
• Functional assays in Mycobacterium smegmatis and in silico studies were conducted to elucidate the mechanism of action.

Main Results:

• A DNA aptamer, APT-6, was identified that binds to Mtb DevR protein.
• APT-6 inhibits DevR-dependent transcription by preventing DevR dimerization and DNA binding.
• In silico analysis showed APT-6 interacts with the C-terminal domain of DevR, crucial for DNA binding and dimerization.

Conclusions:

• APT-6 is the first reported DNA aptamer to inhibit a bacterial cytosolic response regulator.
• APT-6's mechanism of inhibiting DevR dimerization offers a potential strategy to block dormancy pathways in mycobacteria.
• This study highlights the potential of aptamer-based therapeutics against intracellular bacterial targets.