A class of anti-cancer drugs shows promise in treating TB


View:431 Time:2018-04-27


Tuberculosis (TB), a contagious illness caused by a bacterium called Mycobacterium TB (Mtb), is still one of the top killers among mankind, ranking above HIV/AIDS, despite the remarkable advance in prevention, diagnosis, and treatment. The history of the illness dates back to thousands of years ago, but until now the war against it is still going on.

Duke scientists recently have demonstrated that a class of anti-cancer drugs, known as matrix metalloproteinase inhibitors, have the potential to fight TB. The matrix metalloproteinase, or MMP, is a type of enzyme responsible for degrading extracellular matrix proteins. MMPs are involved in normal cell activities and functions, including cell proliferation, migration, differentiation, angiogenesis, apoptosis, host defense, wound repair, growth and tissue development. But these enzymes have also been linked to diseases. In cancer, overexpression of MMPs is often correlated with metastasis. Lots of MMP inhibitors have been developed for cancer treatment but many of them failed to work in clinical trials.

A characteristic of the human TB granuloma is extensive tissue remodeling. MMPs are key players in this remodeling process. Several MMPs are expressed at elevated levels in human TB granulomas or tissues, and this MMP increase results from Mtb infection and ultimately triggers granuloma necrosis, previous studies have indicated. However, when tested in Mtb-infected animals, MMP inhibitors led to mixed results. The effect of MMP inhibition on TB granulomas warrants further exploration.

Inspired by these findings, Duke scientists, along with researchers from Cornell University and The State University of New Jersey, evaluated the efficacy of MMP inhibitors in murine TB granuloma models. They found that small molecule MMP inhibitors improved the structural integrity of leaky blood vessels, leading to an increased delivery of anti-TB drugs in the lung, which resulted in enhanced drug efficacy. MMP inhibitors increase the killing activity of two commonly used antibiotics against TB -- isoniazid and rifampicin.

In summary, the study demonstrates that MMP inhibition can increase the efficacy of anti-TB drugs in vivo. Some MMP inhibitors are cheap and well-tolerated and their side effects may be prevented. Combining these MMP inhibitors with existing anti-TB drugs would improve TB treatment.

The full paper (Matrix metalloproteinase inhibitors enhance the efficacy of frontline drugs against Mycobacterium TB) can be read in PLOS Pathogens.

According to one of the senior authors of the study, Xiling Shen at Duke University, previous research is largely aimed to use antibiotic therapies to kill the pathogen causing TB. Their new study, instead, tried to target host factors involved in the disease.

At present, patients with active TB are usually treated with a combination of several anti-TB drugs for at least half a year in order to kill all the disease-causing bacteria and prevent the emergence of drug resistance. However, many of them fail to stick to the medication schedule and therefore are more likely to develop drug-resistant TB. More effective treatment regimens would facilitate the treatment and prevention of TB.
 
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