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Breakthrough in tuberculosis treatment

20 May 2021
A team of microbiologists from VU Amsterdam and the Centre for Structural Systems Biology in Hamburg discovered how the tuberculosis bacterium manages to hide from our immune system. This discovery will potentially lead to new drugs and is therefore a breakthrough in the fight against tuberculosis.

Under the leadership of Edith Houben and Wilbert Bitter, the researchers used electron microscopy to reveal the transport mechanism of the tuberculosis bacterium for the first time ever. The bacterium uses this mechanism to spread various substances that harm our body. The discovery can be used to develop new types of antibiotics that can block this transport mechanism and represents a breakthrough in the fight against this contagious disease, which mainly occurs in Southeast Asia, South Africa and Russia. The findings were published in the journal Nature.

1.5 million fatalities
Tuberculosis spreads easily in densely populated areas such as prisons and slums when someone infected with tuberculosis coughs. Partly because of this, tuberculosis is currently the world’s deadliest bacterial infectious disease, causing around 1.5 million fatalities annually.

Resistance
The tuberculosis bacterium mainly infects the lungs, where it invades our immune cells, the macrophages, and hides there. Thanks to this hiding place and the slow rate of cell division, the infection is difficult to fight with antibiotics. This is because most antibiotics act on rapidly dividing cells. Antibiotic treatments for tuberculosis therefore take a long time to work – at least six months – and so many people fail to complete the course. This allows the bacteria to become resistant, which is a growing problem throughout the world.

Balance disturbed
The tuberculosis bacterium also upsets the metabolism of the macrophages. By using the transport mechanism to spread molecules in the macrophage, the bacterium can survive longer in the infected tissue and manipulate the human immune response. Eventually, the infection becomes encapsulated in a clot of immune cells called a tubercle or granuloma. In healthy people, this amounts to a truce between the bacterium and our immune system and they do not notice that they are infected at all. This is called latent tuberculosis and is very common worldwide.

Open tuberculosis
In people with less resistance, this balance is disturbed and the bacteria can spread, causing open tuberculosis. This disease inhibits the lungs and ultimately leads to the death of the patient if no effective antibiotic treatment is provided. New antibiotics that prevent the tuberculosis bacteria from defending themselves against our immune system, such as transport mechanism inhibitors, could offer a new way to solve the growing tuberculosis problem.

Designing molecules
The knowledge of the structure of the bacterial transport mechanism can now be used by researchers to design molecules that can block these transport systems. “Developing these inhibitory molecules is feasible and can be done in various ways,” explains VU Amsterdam researcher Edith Houben. “The difficulty with this research is that it has to work on intact bacteria and then also during an infection, i.e. inside the human body. It will be several years before such an inhibitor can be clinically tested.”