Some bacteria have a protective shell of cross-linked sugar molecules, which among other things, can ward off certain antibiotics. Researchers at the University of Bonn and the German Centre for Infection Research (DZIF) have now recreated this capsule in a test tube and were able to reveal its weak points. They also represent potential attack points for new drugs. The study is published in the journal Nature Communications.
The capsule is a complex sugar polymer that makes the bacteria invisible to the immune system. Moreover, it acts as a barrier for antibodies, such as certain antibiotics. If the formation of the capsule could be prevented, it would give the pathogens a serious blow. ‘We still know very little about how this capsule is created’, explains Prof. Dr Tanja Schneider from the Institute of Pharmaceutical Microbiology at the University of Bonn.
With the recently published study, the scientists have taken a big leap towards ‘recreating’ the capsule of the widespread Staphylococcus aureus in a test tube. Staphylococci are among the so-called gram-positive bacteria, which are distinguished by the specific structure of their cell wall and their ability to form a capsule.
Shell based on the ‘onion principle’
In simple terms, Staphylococcus is surrounded by three different enveloping layers. The innermost of these is the membrane, a razor-thin, fat-like membrane. It is enveloped by a wall of closely linked sugar-peptide fibres, the so-called murein. The capsule is the outermost layer. The fact that 16 different enzymes are involved in its formation was already known. The enzymes are attached to, and in, the membrane and only function in this state – a key reason why they are so hard to examine. To do this, the researchers isolated the capsule enzymes, purified them and placed them in a test tube with membrane components. ‘This method allowed us to analyse the catalysed reactions as well as to investigate how they are coordinated’, explains Schneider's colleague Dr Marvin Rausch.
The group, which also includes researchers from England and the United States, has made a few unexpected discoveries. It appears that the capsule synthesis relies on a type of delivery service, which brings starting materials to the corresponding enzymes. Interestingly, this delivery service is also used for a different purpose: as a supplier for murein wall synthesis. ‘This wall is vital to most bacteria’, emphasises Schneider. ‘The capsule in Staphylococcus aureus must therefore not be synthesized until the wall is finished.’
An enzyme called PknB ensures that this sequence is followed. As long as the delivery service still carries murein components, PknB ensures that the capsule synthesis remains switched off. But then the bacterium radically switches over: As soon as capsule production begins, another enzyme called CapA takes over. This catalyst is additionally activated by capsule intermediates. This puts a positive feedback loop in motion, which essentially spurs CapA to a maximum.
New active substances urgently needed
Both CapA and PknB perform important functions in capsule synthesis. They may therefore be suitable as a target for new drugs. ‘We also identified a molecule that anchored the capsule to the murein wall’, says Schneider. ‘This may unveil yet another therapeutic option.’
Next, the scientists want weed through huge substance libraries to search for agents that can be effectively deployed against the found structures. However, even under ideal circumstances, it will take many years before this will produce new drugs. ‘Nevertheless, this work is extremely important’, explains Schneider. ‘Even though various measures have indeed made it possible to get a better grip on infections caused by staphylococci, experience teaches us not to take it for granted: at some point, new resistances will emerge, and we should be prepared for them.’
Source: Press office of the University Of Bonn