Novel Anti-Tuberculosis Strategies: Targeting Shikimate Kinase for Effective Therapy

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a global health challenge due to drug resistance and the long duration of current treatments. A promising target for novel anti-TB therapies is shikimate kinase (MtSK), an essential enzyme in the shikimate pathway, which is crucial for Mtb survival and virulence but absent in mammalian homologue. Recent advances in structural biology and computational chemistry have identified several novel MtSK inhibitors with diverse structural features. Shikimic acid analogs, despite their structural similarity to endogenous shikimate, inhibit MtSK by preventing the transfer of phosphate from ATP to shikimate. Other inhibitors include compounds with Chalcones, pyrazolone, oxadiazole-amide, and 2-aminobenzothiazole frameworks. Notably, the dipeptide +H3N-Arg-Asp-COO– (RD) has shown superior binding affinity compared to shikimate, forming unique interactions with MtSK in both open- and closed-lid conformations. This review delves into the structural and functional insights of these novel inhibitors, shikimate kinase as a potential target emphasizing their potential in developing more effective and targeted anti-TB therapies.