The emergence of antimicrobial resistance among tuberculosis (TB) harshly impairs TB control. Fluoroquinolones (TB) are one of the core antibiotics used to treat MDR-TB. Analysis of structure activity relationship among a series of lipophilic analogues of FQ recently synthesized revealed 2 molecules (HIT18 and 19) that remain fully active against clinical strains resistant to FQ. These data strongly suggest that these HITs have acquired a mode of action different than the one of standard FQ, implicating an uncharacterized TB protein. Therefore, in the particular context of crucial need of new anti-tuberculous drugs, we set up a consortium of highly experienced research teams that will address the mode of action, the evasion mechanisms, and the optimization of the structure and activity of this promising new class of molecules through a multidisciplinary approach merging pharmacology, microbiology, fluorescence microscopy, genomic, proteomic, and biochemical studies.