Antibiotic-resistant bacterial strains are multiplying. To forestall a serious public health problem, new molecules must be developed. At the de Duve Institute, Jean-François Collet and his team made a discovery, published in PloS Biology, that could disarm antibiotic-resistant bacteria.
We have known it for a long time: living beings evolve and adapt to resist adversity, otherwise they will disappear – a survival instinct that applies no less to bacteria. While the discovery of penicillin and its use as an antibiotic since the 1940s has undermined bacterial resistance, treatment-resistant bacterial infections are now developing all over the world. Hence antibiotics must evolve. ‘We must find new antibacterial molecules’, says Jean-François Collet, a de Duve Institute researchers and bacteria specialist. ‘Because it is predicted that within 10, 20 or 30 years, antibiotic-resistant bacteria will pose a public health problem.’
He finds that all too often the impact of antibiotics on society is underestimated. ‘They have profoundly changed human life. They have saved millions of lives, allowing for treatment or avoidance of bacterial infections in surgical operations. Today, the number of bacterial strains resistant to antibiotics continues to increase. By 2050, bacteria could be more lethal than cancer! However, pharmaceutical companies have divested this field for 20 or 30 years and too few new antibiotics have emerged on the market in the last 15 years. There is a real danger. Hundreds of laboratories around the world are now trying to find possibilities for developing new antibiotics.’
Understand in order to disarm
It is in this context that Prof. Collet directs his research. And with his team, he has just made a discovery that is the subject of an article published in the American journal PloS Biology. ‘From a fundamental point of view, we have discovered a very elegant mechanism used by bacteria to protect themselves optimally against certain toxic molecules. Energised by our discovery, we launched a research programme to try to find out how to use it in the identification of new antibacterial molecules.’ In his de Duve Institute laboratory, Prof. Collet’s team seeks to understand how bacteria respond to external attacks, so that they can better disarm them and determine how to move beyond their defence mechanisms.
To explain his discovery, he compares the gram-negative bacteria he studies to castles: they are surrounded by a double wall: a double membrane that protects them from external attacks. The research aim is to understand the composition of this double wall and determine whether the distance between the two walls is an important factor for bacteria.
Disrupting the work of sentries
‘We managed to manipulate these microscopic bacteria here in the lab, working in collaboration with the University of Utah. We managed to increase the distance between the two membranes that make up the bacterial envelope and to show that the bacterium was disrupted.’
A bacterium is made of proteins, which are present inside it or on its surface. Some are posted like sentries on what Prof. Collet compares to the exterior wall, and their function is to sound the alarm when a problem occurs. ‘When the antibiotic enemy attacks, they manage to detect it and communicate the information to a colleague positioned inside the compound, which in turn transfers the information to the control centre. If we increase the distance between the walls of fortification, the message no longer passes. It’s as if they had communicated by touching each other, then were pushed apart. Protein size is therefore adapted to the distance between these walls.’
Faulty alarm system
The researchers were able to determine that communication was restored when they provided ‘a longer arm’ to the proteins, allowing them to touch each other again. ‘It’s an amazing but very simple discovery. Research on sizes and distances. If we don’t extend the sentry protein, it can no longer sound the alarm. So if we manage to find a molecule that altering the castle’s architecture, we disrupt the entire alarm system. The bacteria are attacked but do not have the ability to detect the attack. This discovery could therefore contribute to the development of a new antibiotic capable of fighting bacteria.’
This lab work could not have been completed without the collaboration of Imperial College London and the University of Utah, nor without funding by WELBIO, the Walloon Virtual Institute for Research Excellence in Life Sciences. And it is far from over. ‘From a fundamental point of view, we will now continue to try to see how the bacterium adapts to a greater and greater distance between the walls.’ And in terms of antibiotic therapy, contacts have been made with pharmaceutical companies. In the coming months, the work should continue with the search for molecules capable of altering bacterial architecture.
A glance at Jean-François Collet's bio
Jean-François Collet is a chemical and agricultural industry engineer at UCL. He did his PhD work at the de Duve Institute. During his thesis work in the laboratory of Prof. Van Schaftingen, he discovered one of the largest families of phosphotransferases. In 2001, he joined Prof. Bardwell’s laboratory (Howard Hughes Medical Institute, University of Michigan), where he worked on the oxidative folding of proteins in the bacterial envelope and developed a new pathway for the formation of disulphide bridges in the periplasm (published in Science in 2004). In 2005, he launched a research group at the de Duve Institute where he studied the mechanisms involved in the assembly and protection of the bacterial envelope. Several major discoveries were made, such as the discovery of two new enzymatic pathways protecting bacterial envelope proteins from oxidative stress (published in Science in 2009 and Nature in 2015) and the discovery of a mechanism to export proteins to the surface of some bacteria (published in Cell in 2014).