We investigated the mechanism of action of an arylsulfonamide with whole-cell activity against Mycobacterium tuberculosis. We newly synthesized the molecule and confirmed it had activity against both extracellular and intracellular bacilli. The molecule had some activity against HepG2 cells but maintained some selectivity. Bacterial cytological profiling suggested that the mechanism of action was via disruption of cell wall synthesis, with similarities to an inhibitor of the mycolic acid exporter MmpL3. The compound induced expression from the IniB promoter and caused a boost in ATP production but did not induce reactive oxygen species. A mutation in MmpL3 (S591I) led to low-level resistance. Taken together, these data confirm the molecule targets cell wall biosynthesis with MmpL3 as the most probable target.
Keywords: MmpL3; antitubercular; cell wall; mode of action; mycobacteria; tuberculosis.