Dual-Acting Small-Molecule Inhibitors Targeting Mycobacterial DNA Replication

Area of Science:

• Microbiology
• Drug Discovery
• Molecular Biology

Background:

• Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a major global health threat, with over 1.5 million deaths annually.
• The rise of antibiotic-resistant Mtb strains necessitates the urgent development of new therapeutic strategies.
• Targeting essential bacterial enzymes involved in DNA replication presents a promising avenue for novel anti-TB drug development.

Purpose of the Study:

• To design and synthesize novel small-molecule inhibitors targeting two essential DNA replication enzymes in Mtb: DnaG primase and DNA gyrase (Gyr).
• To optimize these inhibitors for improved physicochemical properties and enhanced inhibitory activity against Mtb enzymes.
• To evaluate the inhibitory potential of the synthesized compounds against both pathogenic Mtb and the model organism Mycobacterium smegmatis (Msmg).

Main Methods:

• Leveraged previously identified inhibitors of T7 DNA primase as a starting point for designing Mtb-specific compounds.
• Synthesized 49 novel compounds through a three-stage chemical optimization process.
• Assessed the inhibitory activity of the synthesized compounds against Mtb DnaG primase and DNA gyrase, as well as Msmg.

Main Results:

• Successfully synthesized 49 novel small-molecule compounds.
• Identified two lead compounds demonstrating potent inhibitory activity against both Mtb DnaG primase and DNA gyrase.
• These two inhibitors also exhibited significant inhibitory effects against Mycobacterium smegmatis, indicating broad-spectrum potential.

Conclusions:

• The developed small-molecule inhibitors represent promising new drug candidates for the treatment of tuberculosis.
• Targeting the conserved TOPRIM fold of Mtb DnaG primase and DNA gyrase is an effective strategy for developing novel anti-TB agents.
• The identified inhibitors warrant further investigation for their efficacy and safety in preclinical and clinical settings.