InhA Targeting Strategies in Antitubercular Drug Development

The enoyl-acyl carrier protein reductase InhA is a pivotal enzyme in the biosynthesis of mycolic acids, which form the robust cell envelope of Mycobacterium tuberculosis. InhA has long been the primary target of isoniazid, a frontline pro-drug that requires activation by the catalase-peroxidase KatG. Mutations in KatG and other resistance mechanisms have diminished isoniazid efficacy, driving the search for direct inhibitors of InhA that bypass activation. Structure-based design and fragment-growing approaches have yielded compounds with nanomolar affinity, extended residence times and cofactor-independent binding modes. Scaffold diversification—incorporating hydrazide-hydrazone, thiadiazole and thiazolino-pyridone cores—has expanded chemical space and improved potency against drug-resistant strains. Complementary adjuvant strategies aim to render M. tuberculosis intrinsically more vulnerable to InhA inhibition by disrupting energy metabolism or cell-wall homeostasis. Together, these efforts seek to deliver novel agents that overcome resistance, shorten treatment regimens and address the global challenge of multidrug-resistant and extensively drug-resistant tuberculosis.

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InhA Targeting Strategies in Antitubercular Drug Development publication trend

The graph below shows the total number of articles in inha targeting strategies in antitubercular drug development across all publications each year (not limited to Nature Index journals).

Technical terms

InhA: Enoyl-[acyl-carrier-protein] reductase essential for mycolic acid synthesis in M. tuberculosis.

Isoniazid (INH): Frontline antitubercular pro-drug that inhibits InhA after activation by KatG.

Pro-drug: Inactive precursor converted in vivo to an active pharmacophore.

Mycolic acids: Long-chain fatty acids that confer impermeability and resilience to the mycobacterial cell wall.

KatG: Mycobacterial catalase-peroxidase enzyme responsible for activating isoniazid.

References

1. Design, Synthesis, and Evaluation of Novel Δ2‑Thiazolino 2‑Pyridone Derivatives That Potentiate Isoniazid Activity in an Isoniazid-Resistant Mycobacterium tuberculosis Mutant. Journal of Medicinal Chemistry (2023).
2. Inducing vulnerability to InhA inhibition restores isoniazid susceptibility in drug-resistant Mycobacterium tuberculosis. mBio (2024).
3. Recent Advances in Anti-Tuberculosis Drug Discovery Based on Hydrazide–Hydrazone and Thiadiazole Derivatives Targeting InhA. Pharmaceuticals (2023).
4. A Slow, Tight Binding Inhibitor of InhA, the Enoyl-Acyl Carrier Protein Reductase from Mycobacterium tuberculosis *. Journal of Biological Chemistry (2010).
5. Discovery of a cofactor-independent inhibitor of Mycobacterium tuberculosis InhA. Life Science Alliance (2018).
6. Fragment-Based Design of Mycobacterium tuberculosis InhA Inhibitors. Journal of Medicinal Chemistry (2020).