New Insight into the Mechanism of Action of and Resistance to Isoniazid: Interaction of <i>Mycobacterium </i><i>tuberculosis </i>enoyl-ACP Reductase with INH-NADP

The Mycobacterium tuberculosis inhA-encoded enoyl-ACP reductase is inhibited by isonicotinoylated-NADP (INH-NADP) with a Ki of 130 nM. The crystal structure of the InhA:INH-NADP complex was solved. The structure revealed that it is the acyclic 4S isomer of INH-NADP that binds to the enzyme in a conformation similar to the InhA:INH-NAD complex solved previously. The in vivo implications of the mechanism of action of and resistance to isoniazid resulting from the dual ability of InhA to bind to INH-NAD and INH-NADP with high affinity are discussed.