The increasing prevalence of multidrug-resistant strains of Mycobacterium
tuberculosis is the main contributing factor in unfavorable outcomes in the
treatment of tuberculosis. Studies suggest that direct inhibitors of InhA, an
enoyl-ACP-reductase, might yield promising clinical candidates that can
be developed into new antitubercular drugs. In this review, we describe the
application of different hit-identification strategies to InhA, which clearly
illustrate the druggability of its active site through distinct binding
mechanisms. We further characterize four classes of InhA inhibitors that
show novel binding modes, and provide evidence of their successful target
engagement as well as their in vivo activity.