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Tuberculosis (TB) is a deadly bacterial infection that remains a global health concern, resulting in millions of deaths each year. Even with treatment, deaths can occur due to drug resistance in TB bacteria and poor delivery of TB-targeting drugs to infected lung tissue. To address these challenges, a team led by researchers at Massachusetts General Hospital (MGH) collaborated with scientists from various institutions to repurpose approved drugs originally tested to normalize blood vessels surrounding tumors. This research, published in the Proceedings of the National Academy of Sciences, aimed to improve drug delivery to TB bacteria and enhance the effectiveness of anti-microbial medications.

The team focused on understanding and overcoming the physiological barriers to drug delivery in pulmonary granulomas, the sites of TB disease that manifest as abnormal lung masses. These abnormalities include poorly functioning blood vessels and an overabundant extracellular matrix, which reduce blood flow and drug delivery to granulomas where TB bacteria reside and evade attack by the immune system. By testing host-directed therapies (HDTs) such as bevacizumab and losartan in a lab model of TB, the researchers aimed to normalize these barriers and improve drug delivery to the bacteria fueling the disease.

Previous research by the team had shown that bevacizumab could improve drug delivery to TB granulomas. In the latest study, combining bevacizumab and losartan in rabbits with TB enhanced TB drug delivery, promoted anti-bacterial host responses, and led to improved health outcomes. Surprisingly, the HDTs themselves were able to reduce bacteria numbers in TB granulomas, indicating potential efficacy as a treatment for TB. Analysis of granuloma and lung tissues revealed that the HDTs promoted inflammatory responses against TB bacteria in both immune and non-immune cells in the lung.

The fact that bevacizumab and losartan are approved, safe, and affordable drugs paves the way for direct clinical translation to test these HDTs in patients with TB. The study’s results suggest that these drugs could improve the outcomes of anti-bacterial therapy for TB patients by enhancing drug delivery to the bacteria and promoting host responses against the infection. The multidisciplinary team of researchers involved in the study included experts in engineering, cancer biology, immunology, microbiology, and data analysis who collaborated to investigate the potential of HDTs in improving TB treatment outcomes.

Study co-authors, including Meenal Datta, Laura E. Via, Véronique Dartois, and others, played a crucial role in identifying mechanisms involved in the efficacy of HDTs in TB treatment. Supported by grants from the Bill & Melinda Gates Foundation and the National Institutes of Health, this research represents a significant advancement in the understanding of TB treatment and the potential for utilizing existing drugs in new ways to combat this deadly bacterial infection. The team’s findings lay the groundwork for further clinical trials to assess the effectiveness of these HDTs in improving outcomes for patients with TB.

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