Salicylate-based drugs as adjuvants to potentiate bedaquiline's anti-TB activity

The National Institute of Allergy and Infectious Diseases awarded Weill Medical College of Cornell University $442,146 on February 6, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to investigate salicylate-based drugs as adjuvants to potentiate bedaquiline's anti-tuberculosis activity.

The project addresses rising rates of low-level resistance to bedaquiline, the current backbone of second-line regimens for drug-resistant tuberculosis. Preliminary data show that salicylate, the principal metabolite of aspirin, enhances bedaquiline's anti-TB activity at concentrations readily achievable in humans. The research aims to quantify this effect, identify optimal salicylate and bedaquiline concentrations for maximal anti-TB activity, and explore whether other salicylate-based NSAIDs with stronger proton-shuttling properties enhance the combination's potency. The work operates through three aims: quantifying the synergistic effect in mycobacterial models, identifying lead compounds among salicylate-based NSAIDs, and elucidating the mechanism by which salicylates shuttle protons from the intermembrane space into the cytoplasm to deplete ATP levels and acidify the mycobacterium tuberculosis cytoplasm.

Work is performed in New York, New York. The period of performance extends from the award date through January 31, 2028. This is a Project Grant, an assistance type supporting investigator-initiated research in infectious diseases.

Abstract

In 2022, over 10 million individuals were diagnosed with tuberculosis (TB) and 1.3 million died of the disease. Approximately 4% of these infections consisted of drug resistant TB (DR TB; defined as rifampin or multidrug resistance), which accounted for a disproportionate 12% of TB-related deaths. A major advancement in the treatment of DR TB came with the approval of bedaquiline, a new mycobacterial ATP synthase inhibitor that is the current backbone of second-line regimens. Addition of bedaquiline to second-line regimens has decreased mortality in patients with DR TB and reduced the length of treatment to 6 months. Newer bedaquiline-based combination therapies are now being investigated as potential short-course universal treatment regimens for TB. Rising rates of low-level resistance to bedaquiline threatens these recent gains. Strategies that boost bedaquiline's anti-TB activity may therefore have relevance for further shortening bedaquiline- based anti-TB regimens to less than 6 months and for combatting existing low-level resistance. Our preliminary data shows that the principal metabolite of aspirin, salicylate, enhances bedaquiline's anti-TB activity at a concentration readily achievable in humans. Salicylate may achieve this effect by shuttling the resulting buildup of protons (from bedaquiline's inhibition of ATP synthase) from the intermembrane space into the cytoplasm. This can kill mycobacterium tuberculosis (MTB), the causative agent of TB, by further depleting ATP levels and acidifying the MTB cytoplasm. The aim of this proposal is to quantitate, validate, and better understand how salicylates potentiate bedaquiline's anti-TB activity. The first aim is to quantify this effect in order to identify salicylate and bedaquiline concentrations that result in best anti-TB activity. We will also explore whether other salicylate-based nsaids with stronger protonophoric activity show stronger or more potent potentiation of bedaquiline; and to what extent this potentiation restores bedaquiline's activity in clinical MTB strains with low-level bedaquiline resistance. In the second aim, we will test the hypothesis that salicylates' aforementioned shuttling of protons is its mechanism of action for boosting of bedaquiline's activity. In the final aim, we will translate our findings by utilizing a macrophage infection model that better approximates the environment and stressors MTB faces upon infection. These three aims will provide crucial preliminary data to justify progression of at least one of these salicylates into animal models, with the ultimate goal of human trials, with the aim of shortening existing bedaquiline-based regimens and addressing the most common form of resistance in the near term.