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Attack from all sides

Tuberculosis – a disease that knows no boundaries, kills millions of people per year worldwide and is developing resistance to current drug therapies at an alarming rate. In order to develop urgently needed new treatment regimes, it is critical to achieve a complete understanding of how Mycobacterium tuberculosis (Mtb) – the bacterium that causes the disease – infects, survives and develops. But despite decades of considerable global research efforts, the mechanisms by which Mtb infects and survives in the human body are still largely a mystery.

Scanning electron micrograph of Mycobacterium tuberculosis bacteria, which cause TB.
Scanning electron micrograph of Mycobacterium tuberculosis bacteria, which cause TB. IMAGE: NIAID (CC BY 2.0)

For such a widespread and complex problem, a multi-disciplinary research approach seems the way to go. A paper published today in the journal PLoS Pathogens by Matthias Wilmanns and collaborators from Switzerland, Poland, and France, illustrates the power of bringing together specialists in different areas.

A global problem

Twenty years ago the World Health Organisation declared Tuberculosis (TB) a global public health emergency. Since then there has been considerable effort to reduce the number of new cases and associated deaths. Although both are decreasing in most parts of the world, TB still remains a major global health concern: in 2013, an estimated nine million people worldwide developed TB and 1.5 million people died from the disease, making it a major cause of death from an infectious disease, second only to HIV/AIDS. The bacterium, Mtb, usually infects the lungs and is spread through the air, for example via coughing or sneezing. Although about one-third of the world’s population has come into contact with it, relatively few people will actually develop the disease. Mtb can remain dormant and almost undetected in the human host for years, even decades, before any symptoms develop.

Tuberculosis can be treated effectively with a six-month course of multiple antibiotics. However, in part because of incomplete and foreshortened treatment, cases of ‘multidrug-resistant TB’ and ‘extensively resistant TB’ are rising. In such cases, treatment is far less successful, requiring more expensive and toxic drugs over an extended period. In Europe, while the overall number of TB cases is decreasing, since 2005 the incidence of drug resistant strains has risen significantly, from 1% to 11% of all cases.

Although it is known that people with a suppressed immune system, such as those with HIV, have a greater risk of developing TB, what exactly triggers the disease to arise from the dormant state is a puzzling and long-standing question. The underlying processes of infection and persistence are still poorly understood despite years of global research effort. The first effective treatment was developed in the 1940s and very few new drugs have been introduced to the market since. As increasing drug resistance bears witness, the need for new, alternative treatments is becoming ever more urgent.

Symptoms of tuberculosis
Symptoms of tuberculosis, from a health bulletin issued in 1918. IMAGE: Government & Heritage Library, State Library of NC (CC BY 2.0)

Complex research

In 2010, TB researchers from across Europe tried a new approach to managing this complex and unusual organism. Thirteen partners, each renowned in their own right for their work on TB, joined forces to set up an interdisciplinary project funded by the European Commission – SysteMTb – with the aim of better understanding the bacterium as a whole, and how it infects humans. One area of research has focused on its unusual cell wall, a thick waxy layer made up of very long lipid chains that protect Mtb from toxic substances, preventing invaders and from entering the cell and causing it harm. This structure could also explain why and how the bacterium can remain dormant and undetected for so long. Understanding how this protective layer works and how it could potentially be broken down could pave the way for new drug therapies. Matthias Wilmanns, Head of EMBL Hamburg, and collaborators focused their efforts on a group of enzymes known as Acyl CoA carboxylases, which are involved in assembling lipids like the ones in Mtb’s cell wall.

To build up a complete picture of how Mtb’s cell walls are made, we need a thorough and systematic analysis of all potential interactions between these proteins

In Mycobacteria such as Mtb, many enzymes involved in assembling other molecules are themselves not single proteins but large sets of proteins known as complexes. These bacteria appear to have an unusually high number of genes that could code for numerous potential complexes – but the exact composition and function of many of those is not known. “To build up a complete picture of how Mtb’s cell walls are made, we need a thorough and systematic analysis of all potential interactions between these proteins,” explains Wilmanns. “Mtb is such a complex and unusual organism, we need to collect as much information as possible about how it all works if we are to design effective new drugs. It’s not enough to simply know the structure of one enzyme – we need to know how it works, and how it works together with other bacterial components.” After identifying potential enzyme complexes, Wilmanns and his coauthors decided to study the AccD1-AccA1 complex – a complex with unknown function.

Unexpected outcomes

Across Europe, a regular exchange of information and samples took place as the groups applied their diverse expertise and approaches to determining the function and biology of the complex. As a first step, the Wilmanns group in Hamburg asked colleagues at the Polish Academy of Sciences in Warsaw to systematically analyse the interaction patterns of more than a dozen genes. As the result, four Acyl CoA carboxylase complexes were found. They then selected one of these complexes – AccD1-AccA1 – and looked to see if, and what, function was lost when the respective genes were deleted. Genetically engineered Mtb strains were initially sent to the Centre National de la Recherche Scientifique (CNRS) in Toulouse, where scientists compared the lipid composition of the cell wall of the strains with no AccD1-AccA1 with that of ’normal’, unmutated Mtb. The results were unexpected: the researchers found no difference in lipid composition.

We found this enzyme is involved in a completely different process

So, if the complex doesn’t build lipids, what does it do? To find out, the group from the Institute of Molecular Systems Biology in Zurich used mass spectrometry to determine what other molecules from Mtb were associated with the enzyme’s function. “We found this enzyme is involved in a completely different process,” says Wilmanns. In fact, all data collected by the groups show that the enzyme is not involved in assembling lipids at all, but is required for the degradation of an essential amino acid – one of the building blocks used to make proteins, not lipids – called leucine. Arjen Jakobi, an EMBL interdisciplinary postdoctoral fellow working across both Wilmanns’ lab and Carsten Sachse’s group at EMBL Heidelberg, then used electron microscopy to determine the overall architecture of the enzyme. This microscopy analysis showed the enzyme to have a four-layered arrangement, similar to that which had already been observed in other enzyme complexes known to play a role in amino acid degradation, further verifying the idea that this is indeed AccD1-AccA1’s function.

Teamwork triumphs

While the research may not have led directly to the identification of potential drug targets, Wilmanns is keen to highlight that this is an important step towards understanding Mtb. “As far as we know this is the first demonstration that Mycobacteria have a specific pathway for degrading leucine, so even though this is not the answer we were expecting, it’s great to be able to add one more piece to the puzzle. And it will help to find more specific inhibitors against other complexes of this protein group.” However, perhaps as important as the results themselves, has been to show how powerful a multidisciplinary and complementary approach has been in the field of tuberculosis research. “Without the work and results from each group, we would not have been able to build up a complete picture of how this enzyme works. This is really the way future research will, and should be done,” says Wilmanns. “Only by approaching such multifaceted problems from all angles, and pooling all our expertise can we get to the bottom of it all.”

Tags: Hamburg, Health, press release, Structural Biology, Wilmanns

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