Shikimate Pathway Inhibition in Mycobacterial Systems

The shikimate pathway is an essential biosynthetic route in Mycobacterium tuberculosis and related species, responsible for the production of aromatic amino acids and a range of key metabolites absent in humans. Inhibition of this pathway offers a promising route to selective antitubercular chemotherapy, exploiting enzymes such as 3-dehydroquinate synthase, shikimate kinase and chorismate synthase that have no human counterparts. Recent structural, kinetic and cellular studies have illuminated the binding pockets and conformational dynamics of these enzymes, guiding the rational design of small-molecule inhibitors. By targeting multiple steps in the pathway, novel compounds have demonstrated activity against both drug-sensitive and multidrug-resistant strains. The global burden of latent and active tuberculosis, coupled with rising resistance, underscores the urgency of translating these enzymological insights into new treatments with improved efficacy and diminished toxicity.

Research from Nature Portfolio

A landmark study identified IMB-T130 as a potent inhibitor of Mycobacterium tuberculosis 3-dehydroquinate synthase (MtDHQS). Biophysical assays confirmed tight binding, while molecular docking and site-directed mutagenesis delineated key residues in the enzyme’s active site. Overexpression of MtDHQS in mycobacterial cells attenuated the compound’s efficacy, validating the enzyme as the principal target. IMB-T130 exhibited sub-micromolar IC₅₀ values against both standard and drug-resistant clinical isolates, demonstrating the feasibility of targeting early shikimate-pathway enzymes for next-generation antitubercular agents.

Shikimate Pathway Inhibition in Mycobacterial Systems publication trend

The graph below shows the total number of articles in shikimate pathway inhibition in mycobacterial systems across all publications each year (not limited to Nature Index journals).

Technical terms

Shikimate pathway: A seven-step metabolic route in bacteria, fungi and plants that generates chorismate, the precursor of aromatic amino acids and secondary metabolites.

3-Dehydroquinate synthase (DHQS): The enzyme catalysing the conversion of 3-deoxy-d-arabino-heptulosonate 7-phosphate to 3-dehydroquinate in the second step of the shikimate pathway.

Shikimate kinase (SK): An ATP-dependent enzyme that phosphorylates shikimate to shikimate-3-phosphate, representing the fifth step in the pathway and a key regulatory locus.

Chorismate synthase: The flavin-dependent enzyme responsible for the final conversion of 5-enolpyruvylshikimate-3-phosphate to chorismate, a branch point for multiple biosynthetic routes.

IC₅₀: The concentration of an inhibitor required to reduce an enzyme’s activity by 50 percent under defined assay conditions.

References

1. Mycobacterium tuberculosis Shikimate Pathway Enzymes as Targets for the Rational Design of Anti-Tuberculosis Drugs. Molecules (2020).
2. IMB-T130 targets 3-dehydroquinate synthase and inhibits Mycobacterium tuberculosis. Scientific Reports (2018).
3. Isolation of alpha-linolenic acid from Sutherlandia frutescens and its inhibition of Mycobacterium tuberculosis’ shikimate kinase enzyme. BMC Complementary Medicine and Therapies (2016).