Anti-tubercular potential and pH-driven mode of action of salicylic acid derivatives
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- Evaluated articles (Rapid Reviews Infectious Diseases)
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.
Article activity feed
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Anonymous
Review 2: "Anti-tubercular Potential and pH-driven Mode of Action of Salicylic Acid Derivatives"
The reviewers suggested placing findings in a broader context with other SA studies and noted that while the compounds show promise due to low cytotoxicity, additional drug interaction testing would be needed.
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Tanya Parish
Review 1: "Anti-tubercular Potential and pH-driven Mode of Action of Salicylic Acid Derivatives"
The reviewers suggested placing findings in a broader context with other SA studies and noted that while the compounds show promise due to low cytotoxicity, additional drug interaction testing would be needed.
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