DNA Gyrase Inhibition Strategies in Mycobacterium Tuberculosis

DNA gyrase, the sole type II topoisomerase in Mycobacterium tuberculosis, is indispensable for maintaining DNA supercoiling during replication and transcription. Historically, fluoroquinolones have dominated clinical use by stabilising the cleavage complex formed by the breakage-reunion core, yet rising resistance through gyrA and gyrB mutations undermines their efficacy. Contemporary strategies seek to exploit alternative enzyme sites, notably the ATPase activity of the GyrB subunit, and to design allosteric inhibitors that circumvent common resistance hot spots. Advances in virtual and ligand-based screening have yielded new chemical scaffolds, including indole, carbazole and pyrrolo[1,2-a]quinazoline derivatives, with enhanced binding affinities and cellular activity. Biophysical characterisation, encompassing binding thermodynamics and residence-time analyses, informs optimisation of dissociation kinetics and selectivity. Complementary approaches leverage drug repurposing to reveal unexpected inhibitors among anthracyclines and natural products. Integrative use of molecular dynamics simulations, high-throughput enzyme assays and structure-guided medicinal chemistry is now driving the refinement of lead compounds. Such innovations are essential to broaden the anti-tubercular armamentarium, address multi-drug-resistant strains and shorten the duration of therapy.

Research from Nature Portfolio

Recent studies have combined high-throughput virtual screening of natural-product libraries with detailed molecular dynamics and docking analyses to discover competitive inhibitors targeting the GyrB ATPase pocket. A novel pyrrolo[1,2-a]quinazoline scaffold emerged as a top hit, exhibiting superior binding energy and stable interactions with key ATP-binding residues. Structure-guided optimisation of this scaffold delivered a derivative with improved pharmacokinetic and toxicological profiles, enhanced stability in simulation and potent inhibition of DNA supercoiling, underscoring the value of integrating computational and experimental workflows.

DNA Gyrase Inhibition Strategies in Mycobacterium Tuberculosis publication trend

The graph below shows the total number of articles in dna gyrase inhibition strategies in mycobacterium tuberculosis across all publications each year (not limited to Nature Index journals).

Technical terms

DNA gyrase: A bacterial type II topoisomerase that introduces negative supercoils into chromosomal DNA, facilitating replication and transcription.

GyrB ATPase domain: The N-terminal subunit of DNA gyrase responsible for binding and hydrolysing ATP, driving conformational changes required for supercoiling.

Breakage-reunion core (GyrA): The C-terminal subunit mediating DNA strand cleavage and re-ligation during the supercoiling cycle.

Virtual screening: Computational method to evaluate large chemical libraries and predict compounds likely to bind a target protein.

IC50: The inhibitor concentration at which 50% of enzymatic activity is suppressed, a standard metric of potency.

Residence time: The duration an inhibitor remains bound to its target, influencing in vivo efficacy.

Molecular dynamics simulation: Computational technique modelling atomic and molecular motions over time to assess binding stability and conformational changes.

References

1. DNA topoisomerase I and DNA gyrase as targets for TB therapy. Drug Discovery Today (2016).
2. Structural Insights into the Quinolone Resistance Mechanism of Mycobacterium tuberculosis DNA Gyrase. PLOS ONE (2010).
3. Ligand-Based Virtual Screening for Discovery of Indole Derivatives as Potent DNA Gyrase ATPase Inhibitors Active against Mycobacterium tuberculosis and Hit Validation by Biological Assays. Journal of Chemical Information and Modeling (2024).
4. Revealing the Interaction Mechanism between Mycobacterium tuberculosis GyrB and Novobiocin, SPR719 through Binding Thermodynamics and Dissociation Kinetics Analysis. International Journal of Molecular Sciences (2024).
5. Virtual screening, optimization and molecular dynamics analyses highlighting a pyrrolo[1,2-a]quinazoline derivative as a potential inhibitor of DNA gyrase B of Mycobacterium tuberculosis. Scientific Reports (2022).
6. Structure-based drug repurposing to inhibit the DNA gyrase of Mycobacterium tuberculosis.. Biochemical Journal (2020).