A combination of approved drugs enhances the delivery of anti-bacterial medications to treat tuberculosis

Deaths can occur even with treatment, sometimes because of drug resistance in TB bacteria and other times due to poor delivery of TB-targeting drugs to patients' infected lung tissue.

To address the latter challenge, a team led by researchers at Massachusetts General Hospital (MGH) in collaboration with scientists at the National Institute of Allergy and Infectious Disease (NIAID), the University of Notre Dame, and Hackensack Meridian School of Medicine, repurposed approved drugs that they originally tested to normalize blood vessels surrounding tumors to improve drug delivery to cancer cells.

In this latest research, which is published in the Proceedings of the National Academy of Sciences, these drugs effectively enhanced the delivery of anti-microbial medications to kill TB bacteria.

"Our team is interested in understanding and overcoming physiological barriers to drug delivery in pulmonary granulomas, the site of TB disease that manifests as abnormal lung masses. Even the most potent anti-bacterial drug will fail if it cannot reach the bacteria fueling the disease," says senior and co-corresponding author Rakesh K. Jain, PhD, director of the E.L. Steele Laboratories for Tumor Biology at MGH and the Andrew Werk Cook Professor of Radiation Oncology at Harvard Medical School.

Poorly functioning blood vessels and an overabundant extracellular matrix (a network of proteins and other molecules that surround and give structure to tissues in the body) both reduce blood flow and drug delivery throughout granulomas, where TB bacteria reside and hide, evading attack by the body's immune system.

"Our multidisciplinary team of engineers, cancer biologists, immunologists, microbiologists, and data analysts used a lab model of TB, which recapitulates human disease, to test what are called host-directed therapies -- or HDTs -- that 'normalize' the abnormal blood vessels and extracellular matrix in granulomas," says Jain. These HDTs are bevacizumab, which acts on blood vessels, and losartan, which targets the extracellular matrix.

Jain and his colleagues previously showed that bevacizumab could improve drug delivery to TB granulomas. Now they've shown that combining bevacizumab and losartan in rabbits with TB enhances TB drug delivery, promotes anti-bacterial host responses, and improves health outcomes. Surprisingly, the HDTs themselves (without anti-bacterial agents) were able to reduce bacteria numbers in TB granulomas.

To identify the mechanisms involved, the investigators analyzed granuloma and lung tissues and found that the HDTs promoted inflammatory responses against TB bacteria, both in immune and non-immune cells in the lung.

"Because bevacizumab and losartan are approved, safe, and affordable, our preclinical study lays the groundwork for direct clinical translation to test these HDTs in patients with TB for the drugs' ability to improve outcomes of anti-bacterial therapy," says Jain.

Study co-authors include Meenal Datta (co-corresponding author), Laura E. Via (co-first author), Ve?ronique Dartois (co-first author), Danielle M. Weiner, Matthew Zimmerman, Firat Kaya, April M. Walker, Joel D. Fleegle, Isaac D. Raplee, Colton McNinch, Maksym Zarodniuk1, Walid S. Kamoun, Changli Yue, Ashwin S. Kumar, Sonu Subudhi, Lei Xu, and Clifton E. Barry III (co-corresponding author).

This work was supported in part by grants from the Bill & Melinda Gates Foundation and the National Institutes of Health.