A cancer treatment drug currently in clinical trials could strengthen tuberculosis therapy by triggering a more controlled cell death process, potentially reducing lung damage in survivors, according to Johns Hopkins Medicine researchers.
The experimental drug navitoclax, when added to standard tuberculosis (TB) treatments, helped infected cells die through a controlled process called apoptosis rather than the more damaging necrosis that typically occurs in TB infections, the study found.
“Current treatment regimens for TB are lengthy, expensive and leave patients vulnerable to relapse and lung scarring. Our research shows that adding in a host-directed therapy has extraordinary promise to solve these problems,” said study senior author Sanjay Jain, a pediatric infectious diseases specialist at Johns Hopkins Children’s Center and professor of pediatrics in the Johns Hopkins University School of Medicine.
The findings, published in the March 27 issue of Nature Communications, could lead to more effective treatments that reduce the severity of post-TB lung disease, a condition affecting tens of millions of TB survivors worldwide.
Despite being preventable and treatable, tuberculosis has likely reclaimed its position as the world’s deadliest infectious disease, causing an estimated 1.25 million deaths and 10.8 million new cases in 2023, according to the World Health Organization. Hundreds of thousands of these infections resist standard antibiotics.
When Mycobacterium tuberculosis, the bacteria responsible for TB, infects lung cells, it manipulates cell death pathways to its advantage. In early infection stages, infected cells normally undergo apoptosis – a regulated, less damaging form of cell death. However, as infections progress, the bacteria trigger necrosis, an uncontrolled cell death that causes inflammation and damages surrounding tissues.
“While apoptosis could be compared to controlled demolition of a building,” Jain explained, “necrosis is more like destruction by a bomb.”
The TB bacteria accomplish this by prompting infected cells to produce Bcl-2, a family of anti-apoptotic proteins. “This hijack of a typically healthy molecular pathway has significant advantages for M. tuberculosis,” said Medha Singh, the study’s first author and a pediatric infectious diseases fellow in the school of medicine. It creates “necrotic niches within the lung that prevent immune system attacks and allow the bacteria to multiply.”
To test whether inhibiting Bcl-2 could improve TB treatment outcomes, the researchers treated mice infected with M. tuberculosis using standard TB antibiotics – rifampin, isoniazid and pyrazinamide. Some mice also received navitoclax, a Bcl-2 inhibitor currently in cancer clinical trials.
After four weeks, mice receiving both standard antibiotics and navitoclax showed remarkable improvements compared to those on antibiotics alone. They had 40% fewer necrotic lung lesions, and the infection was less likely to spread to other organs like the spleen. The combination treatment also reduced lung scarring by 40%.
Imaging studies using positron emission tomography (PET) showed the addition of navitoclax doubled the amount of pulmonary apoptosis. Though navitoclax had no direct effect on M. tuberculosis when used alone, animals receiving the drug along with antibiotics decreased their bacterial burden 16 times more effectively than those receiving only standard treatment.
These results suggest navitoclax might offer similar benefits for TB patients and those with other chronic bacterial infections prevalent in the U.S., such as Staphylococcus aureus and non-TB mycobacteria,
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