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

Laudouze, J.; Francis, T.; Forest, E.; Mies, F.; Bolla, J.-M.; Crauste, C.; Canaan, S.; Shlyonsky, V.; Santucci, P.; Cavalier, J.-F.

doi:10.1101/2024.09.22.614344

bioRxiv · 10.1101/2024.09.22.614344

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

Laudouze, J.·Francis, T.·Forest, E.·Mies, F.·Bolla, J.-M.·Crauste, C.·Canaan, S.·Shlyonsky, V.·Santucci, P.·Cavalier, J.-F.

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Abstract

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.

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Laudouze, J., Francis, T., Forest, E., Mies, F., Bolla, J.-M., Crauste, C., Canaan, S., Shlyonsky, V., Santucci, P., Cavalier, J.-F.. 2024-09-22. Anti-tubercular potential and pH-driven mode of action of salicylic acid derivatives. https://doi.org/10.1101/2024.09.22.614344

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