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, including M. 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 that SA, 5ISA, 3,5diISA and the anti-inflammatory drug aspirin ( ASP ) act by disrupting the intrabacterial pH homeostasis of M. tuberculosis in a dose-dependent manner under in vitro conditions 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 that SA, ASP and its two iodinated derivatives could restrict M. tuberculosis growth in a pH-dependent manner by acidifying the cytosol of the bacilli; therefore, making such compounds very attractive for further development.