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New Weapons against Multidrug Resistance in Tuberculosis

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In a study carried out by the scientists at the EPFL, scientists have reported that they have discovered two small molecules using a high-throughput screening assay that could overcome the tuberculosis bacteria which are multi drug resistant.

Caused by a bacterium called Mycobacterium tuberculosis (Mtb), tuberculosis is an infectious disease which is characterized by lung infection. It was estimated by the World Health Organization that in the year 2012, tuberculosis affected 8.6 million people world and as many as 1.4 million people succumbed to death due to it. The treatment of tuberculosis typically spans over several months and the process of treatment is often hampered because the bacteria often develop antibiotic resistance. That is the reason why there has been a growing need for finding out alternative medications and drug screening methods. For developing them it is important that the molecular machinery used by Mtb to infect a person is understood in a better way.

The new study at EPFL has discovered two small molecules that show remarkable promise in the fight against tuberculosis. The report on the research has been published in the journal Cell Host & Microbe.

In a person affected with tuberculosis the mycobacterium enters and infects the lung’s immune cells, the macrophages which renders them unable to digest and eradicate the bacterium. Although tuberculosis is an old disease, it is not easy to treat it as current antibiotic regimens last over six months. The biggest hurdle is that in the course of the treatment process, Mtb starts showing increased resistance to drugs.

The team of Stewart Cole at EPFL’s Global Health Institute developed a drug-screening assay which has the ability to explore thousands of compounds simultaneously. The strategy found by the researchers involves targeting the molecular machinery which is used by Mtb to infect lung cells. It has been observed that Mtb uses a specialized secretion system to release “virulence proteins” upon infection. Once secreted, these proteins aid the bacterium in invading the cells of a person’s lungs and replicate itself. They also break down the infected cells, destroy the lung tissue and allow the Mtb to escape and spread.

For this experiment human lung cells were used by the scientists. These cells were grown inside the wells of specialized culture plates. The cells were infected with Mtb and then incubated with different compounds. These compounds had the ability to abolish the cell lysis caused by a potent virulence protein called “EsxA”. They then quantified the survival rate of the cells using fluorescent staining. The researchers were able to screen a total of 10,880 different compounds, from a library of a pharmaceutical company working on tuberculosis.

Cole's team used the screening method and narrowed down the compound to two namely BBH7 and BTP15. These are the ones that showed great promise in their activity against Mtb. It was observed that they were able to inhibit the secretion of the virulence protein EsxA. They also exert multiple effects against the molecular apparatus of Mtb that secretes EsxA and it reduced the functionality of its different components.

What makes this approach different is that rather than trying to kill Mtb, it disarms it to prevent tissue damage remarked Steward Cole. He added that this approach could be used as a part of a larger treatment in combination with conventional drugs. This means that any drugs based on BBH7 and BTP15 would fight against Mtb indirectly as it would help the patient’s immune cells which would then kill the bacterium.

The plan of Cole's team now is that they want to test different combination of compounds to see if they can improve the efficiency of BBH7 and BTP15 against Mtb. Also, they want to apply their screening method on other bacteria.