Medication significantly decreases TB growth, find scientists

Texas Biomedical Research Institute (Texas Biomed) scientists discovered that the medication significantly decreases TB growth, especially in drug-resistant bacteria. The findings, published in the journal Biomedicine & Pharmacotherapy, were made in unique cellular models containing TB-infected human cells, which can aid in the screening of future TB medications and therapies such as this one.

The medication tested in this study comprises two molecules, one of which is already FDA-approved for use in cancer patients and another that is being tested in Phase 1/2 cancer clinical trials.

The substances assist the body in initiating natural cell death processes in specified locations, whether malignant cells or, in this case, cells infected with Mycobacterium tuberculosis (M.tb), the bacteria that causes tuberculosis (TB).

Every year, TB kills more than 1.6 million people worldwide. The bacterium attacks the lungs mostly. Patients must take antibiotics for months to control active infection; drug resistance is on the rise, making treatment even more difficult.

Dr Schlesinger's lab at Texas Biomed is focused on understanding the fundamental biological interactions between airborne-transmissible bacteria and humans and then using those insights to identify potential treatment targets.

M.tb blocks a normal cell death process called apoptosis. This allows the bacteria to grow inside immune cells in the lungs, called alveolar macrophages. This new paper shows that by inhibiting two key proteins, MCL-1 and BCL-2, M.tb can no longer hijack the apoptosis process and macrophages are able to kill M.tb.

Importantly, this happens inside granuloma structures, the dense cellular clumps that the body forms around M.tb to try to contain it. Antibiotics and other treatments have a notoriously difficult time penetrating granulomas, which is one reason why M.tb is so hard to eliminate."Immunotherapy has been a game-changer in the cancer field by finding ways to help a patient's own immune system fight tumours more effectively," said Larry Schlesinger, MD, Texas Biomed Professor, President and CEO, and senior paper author. "We believe that, similarly, host-directed therapies can be a game-changer for infectious diseases."

The research team, led by Texas Biomed Staff Scientist Eusondia Arnett, PhD, tested MCL-1 and BCL-2 inhibitors individually, together and in combination with TB antibiotics to see how TB growth was affected. Using both inhibitors was more effective at limiting TB growth than just one or the other; and combining them with antibiotics was far more effective than either inhibitors or antibiotics alone.

"The inhibitors combined with antibiotics controlled TB up to 98 per cent, which is very exciting," said Dr Arnett, the first paper author. "But even more exciting is the inhibitors were just as effective at controlling drug-resistant TB as drug-susceptible TB. That is the power of a host-directed therapy targeting the human's immune response versus trying to attack the pathogen directly."

A key aspect of the research is the cellular models used to test the effectiveness of the inhibitors: human macrophages and a human granuloma model developed and refined in Dr. Schlesinger's lab over the past decade. Human blood cells donated by volunteers are cultured with M.tb, which leads to the formation of granuloma-like structures.

"Granulomas are unique, dense environments that are not well replicated in mice," Dr. Arnett said. "Our studies demonstrate that this cellular model can serve as an important bridge to identify compounds that can penetrate and retain activity in granulomas, before we move to the necessary - but more complex, time-consuming and expensive - animal research phase."

Dr. Schlesinger and Dr. Arnett have filed a provisional patent for the combination therapy for infectious diseases. They are planning additional cell, mouse and nonhuman primate studies to gather further evidence about the therapy's effectiveness and seek partnerships with industry collaborators. They are hopeful the therapy can move quickly to the clinic because years of safety studies have already been completed, or are underway, for the inhibitors for cancer applications. (ANI)