Thymidine Kinase Inhibitors in Mycobacterial Systems
Summary
Thymidine kinase (TK) is a pivotal enzyme in the pyrimidine salvage pathway of Mycobacterium species, catalysing the phosphorylation of thymidine to thymidine monophosphate, a precursor for DNA replication. Inhibitors targeting mycobacterial TK interfere with DNA synthesis and represent a promising strategy to combat drug-resistant strains of Mycobacterium tuberculosis. Recent efforts have harnessed structure-based design and systematic modification of pyrimidine and purine nucleoside scaffolds to achieve high affinity for the mycobacterial enzyme while minimising off-target effects on human kinases. Key challenges include ensuring selective uptake by the bacterium, overcoming the complex lipid-rich cell envelope of mycobacteria, and retaining activity in the intracellular environment of infected macrophages. Advances in enzymology, biophysical characterisation and medicinal chemistry have begun to yield lead compounds that demonstrate potent bacteriostatic and bactericidal activity against both laboratory and clinical isolates in vitro and in macrophage infection models. Continued optimisation of pharmacokinetic properties, coupled with combination studies alongside frontline tuberculosis therapies, underscores the global significance of TK inhibitors as adjuncts or alternatives in the fight against multidrug-resistant and extensively drug-resistant tuberculosis.
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Thymidine Kinase Inhibitors in Mycobacterial Systems publication trend
The graph below shows the total number of articles in thymidine kinase inhibitors in mycobacterial systems across all publications each year (not limited to Nature Index journals).
Technical terms
Thymidine kinase (TK): Enzyme that phosphorylates thymidine to thymidine monophosphate in the pyrimidine salvage pathway.
Nucleoside analogue: Synthetic compound resembling a natural nucleoside, designed to disrupt nucleic acid metabolism.
Structure–activity relationship (SAR): Correlation between chemical structure modifications and changes in biological potency.
Minimum inhibitory concentration (MIC): Lowest concentration of an antimicrobial that prevents visible microbial growth.
Pyrimidine salvage pathway: Metabolic route recycling free pyrimidine bases and nucleosides into nucleotides.
References
- Derivatives of Pyrimidine Nucleosides Affect Artificial Membranes Enriched with Mycobacterial Lipids. Pharmaceutics (2024).
- New Flexible Analogues of 8-Aza-7-deazapurine Nucleosides as Potential Antibacterial Agents. International Journal of Molecular Sciences (2023).
- Analogues of Pyrimidine Nucleosides as Mycobacteria Growth Inhibitors. Microorganisms (2022).
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