Is Mycobacterial InhA a Suitable Target for Rational Drug Design?

Abstract

InhA, an NAD-dependent enoyl-acyl carrier protein reductase, is involved in the biosynthesis of mycolic acids, specific lipids to mycobacteria. InhA is the target of isoniazid, a first-line anti-tuberculosis drug used since the 1950s. Isoniazid is a prodrug that needs to be activated by the catalase-peroxidase KatG. Due to resistance problems, a substantial amount of work has been carried out to identify or design direct inhibitors of InhA, demonstrating that this enzyme is still considered a relevant target for the discovery of new anti-tuberculosis drugs. Much of this work included the resolution of crystallographic structures. Indeed, over a hundred structures have been deposited in the Protein Data Bank for different forms of the enzyme (apo, holo, and complexes), demonstrating a real crystalline polymorphism. Taken together, these structures constitute a valuable dataset. However, the complete decoding of the enzyme's properties and its inhibition literally comes up agaisnt its molecular plasticity at the level of a motif essential to the definition of the active site: the substrate-binding loop. In this article, we propose a detailed analysis of this structural dataset, describing in particular the different families of inhibitors, and attempt to establish structural links of causality.