Anti-tubercular potential and pH-driven mode of action of salicylic acid derivatives

In the search for new anti-tuberculosis drugs with novel mechanisms of action, we evaluated the antimycobacterial activity of a panel of eight phenolic acids against four pathogenic mycobacterial model species, includingM. tuberculosis. We demonstrated that salicylic acid (SA), as well as the iodinated derivatives 5-iodo-salicylic acid (5ISA) and 3,5-diiodo-salicylic acid (3,5diISA), displayed promising antitubercular activities. Remarkably, using a genetically encoded mycobacterial intrabacterial pH reporter, we describe for the first time thatSA, 5ISA, 3,5diISAand the anti-inflammatory drug aspirin (ASP) act by disrupting the intrabacterial pH homeostasis ofM. tuberculosisin a dose-dependent manner underin vitroconditions mimicking the endolysosomal pH of macrophages. In contrast, the structurally related second-line anti-TB drug 4-aminosalicylic acid (PAS) had no pH-dependent activity and was strongly antagonized by L-methionine supplementation, thereby suggesting distinct modes of action. Finally, we propose thatSA, ASPand its two iodinated derivatives could restrictM. tuberculosisgrowth in a pH-dependent manner by acidifying the cytosol of the bacilli; therefore, making such compounds very attractive for further development.