Fragment-Based Design of Mycobacterium Tuberculosis InhA Inhibitors

Tuberculosis (TB) remains a leading cause of mortality amongst infectious diseases worldwide. InhA, the target of the first line pro-drug isoniazid, an enoyl ACP-reductase, has been the focus of numerous drug discovery efforts attempting to find new clinical candidates that directly inhibit this enzyme and that do not require activation by the catalase peroxidase KatG, thus circumventing the majority of the resistance mechanisms. In this work, we describe the screening and validation cascade of a fragment library and employ a fragment growing strategy using structure-guided fragment-based design to develop potent InhA inhibitors.