Repurposed medications enhance tuberculosis treatment in mice
Drugs known as matrix metalloproteinase (MMP) inhibitors–originally developed for other uses, such as cancer treatment–enhance antibiotic treatment of tuberculosis in mice, according to new research published in PLOS Pathogens by Yitian Xu of Cornell University and colleagues.
Mycobacterium tuberculosis, the bacterium responsible for tuberculosis, kills almost two million people every year. While effective anti-tuberculosis drugs exist, they must be taken for six to nine months, and the difficulty of adhering to treatment during that extended period can promote emergence of drug-resistant strains.
Shortening the tuberculosis treatment period could reduce drug resistance and save lives, and previous research has hinted that adding MMP inhibitors, drugs originally created to combat cancer and other diseases involving connective tissue, could boost the power of standard tuberculosis antibiotics. However, the results of these efforts have been mixed.
To clarify the potential of MMP inhibitors, Xu and colleagues systematically tested them in mice infected with M. tuberculosis. This bacterium causes major changes to host tissue at the site of infection, usually in the lungs. It triggers the immune system to form protective structures known as granulomas, and it causes leaks in nearby blood vessels.
The researchers found that the MMP inhibitors, which block the activity of MMP enzymes that break down connective tissue, improved blood vessel health at the sites of tuberculosis infection in the mice. This resulted in enhanced delivery and retention of the standard tuberculosis drugs isoniazid and rifampicin at granulomas, significantly increasing the amount of bacteria they killed.
MMP inhibitors are relatively affordable and many have already undergone safety testing in humans, making them attractive as a potential strategy to shorten tuberculosis treatment. Further research will be needed to determine if the results seen in mice can be replicated in people.
"The lung forms granulomas to contain the TB infection, but ironically the granulomas also provide TB bacteria shelters from immune surveillance and antibiotics treatment," the authors explain. "The MMP inhibitors restore blood vessels in the infectious site, which provide a conduit for antibiotics to reach and kill the bacteria. This synergy will revitalize current TB treatment and reduce the risk of multi-drug resistant strains."
In your coverage please use this URL to provide access to the freely available article in PLOS Pathogens: http://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1006974
Citation: Xu Y, Wang L, Zimmerman MD, Chen K-Y, Huang L, Fu D-J, et al. (2018) Matrix metalloproteinase inhibitors enhance the efficacy of frontline drugs against Mycobacterium tuberculosis. PLoS Pathog 14(4): e1006974. https://doi.org/10.1371/journal.ppat.1006974
Funding: YX and XS are supported by DOD DARPA 19-1091726, 21-1073697, W911NF-15-1-0609, NIH R35GM122465, R01GM114254, and NSF 1511357. DGR is supported by NIH grants AI134183 and AI118582. VD is supported by Bill and Melinda Gates Foundation grant OPP 1174780. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
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