Endolysins: a new weapon against superbugs?

In recent years, more and more bacteria have become resistant to antibiotics. Medication is losing its effectiveness, and with fatal consequences: every year, more than one million people worldwide die from infections that were still treatable just a few decades ago. According to official federal figures, this leads to 300 deaths in Switzerland every year. A study published in the journal “The Lancet” in 2024 warns that over the coming 25 years, resistant germs could cause more than 39 million deaths globally. “Bacterial infections could then claim more lives than cancer does today,” says Mathias Schmelcher, a molecular biologist at the ZHAW.

The danger is growing quietly and is often underestimated, notes Schmelcher. “If we fail to act, we’ll fall back into the Middle Ages in terms of treating bacterial infections, figuratively speaking at least.” Even small wounds could be life-threatening again if pathogens were to enter. However, modern medicine would also be impacted, for example if antibiotics were to become ineffective during surgeries. One major reason for the development of resistance is the widespread and often inappropriate use of antibiotics in humans and animals.

Alexander Fleming, who discovered penicillin, warned of this development back in 1945 when he received the Nobel Prize. His appeal to consider evolutionary processes went unheard – the medical breakthrough made possible by the first antibiotic was simply too monumental. Penicillin came from a mould fungus. Now, 80 years later, researchers are working intensively to find alternatives. Bacteriophages, or simply phages for short, are one promising candidate. These naturally occurring viruses specifically attack bacteria. In particular, focus is being placed on two approaches: either the entire phage is used as a bacterial hunter or just one of its weapons is deployed, a protein called endolysin.

Schmelcher himself has been researching endolysins for years, initially at the ETH Zurich. He is now contributing his knowledge at the School of Life Sciences and Facility Management, where phage research is already underway. To understand how endolysins work, it helps to take a look at the phage as a whole. When a phage encounters a bacterium, it attaches itself to it and injects its genetic material. “The phage takes control,” says Schmelcher. The reprogrammed bacterium then produces a swarm of new phages. At the end of its replication cycle, the hunter deploys his weapon: to dissolve the bacterium from within.

“As an enzyme, endolysin cuts off chemical bonds in the bacterial cell wall,” explains Schmelcher. The wall becomes unstable and collapses under the internal cell pressure. The bacterium bursts, releasing the young phages. These infest more bacteria – until the infection is defeated. “Phages are harmless to humans, animals and plants because they specifically infect bacteria,” emphasises Schmelcher.

Endolysins are now produced biotechnologically by utilising the genetic blueprint of the phage. “They are also effective against many bacteria when applied externally,” says Schmelcher. Improved properties can also be tailored technologically. Research is still in its infancy, however, and it will be some time before they are used as an active ingredient. Although endolysins have already proven effective in laboratory studies, also in such involving mice, initial clinical studies are still delivering inconsistent results.

Schmelcher sees great potential in endolysins. “Unlike conventional antibiotics, they act with high specificity,” he explains. They only kill the target pathogens and spare beneficial bacteria in the gut or on the skin. Resistance development is, moreover, highly unlikely because endolysins only destroy the cell wall, which is essential for bacteria, making it hard for the pathogens to adapt. “Once on the market, endolysins could remain effective for a long time,” says Schmelcher.

Their application against germs like Staphylococcus aureus is particularly promising. This bacterium often lives harmlessly on our skin and mucus membranes but can cause diseases through wounds or immune deficiencies – from skin abscesses, meningitis and osteomyelitis to life-threatening blood poisoning and inflammation of the inner lining of the heart. In livestock, it frequently causes udder infections. Staphylococcal infections are difficult to treat for two reasons: firstly, certain strains are multi-resistant, meaning they are impervious to several antibiotics. These include MRSA, a superbug that causes problems in hospitals in particular and against which endolysins have been proven effective. Secondly, “staphylococci like to hide in niches,” Schmelcher explains. They live in biofilms on mucus membranes or artificial surfaces like catheters and implants, or they lie dormant in the body's cells before becoming active. Conventional antibiotics hardly reach them there, while endolysins apparently also eliminate dormant pathogens.

What’s more, biotechnologically designed endolysins injected into the bloodstream seem to target the very spots where staphylococci reside. “In animal models, we were able to significantly reduce the number of bacteria in infected bone tissue,” reports Schmelcher. Despite these advantages, questions remain – and Schmelcher is also working on them. For example, the body quickly breaks down endolysins or excretes them, limiting their effect over time. The immune system could also form antibodies that render further treatments ineffective.

If the technical hurdles are overcome, regulatory obstacles will follow because the authorities must determine whether a preparation is effective and safe enough to be approved as a medicinal product. For endolysins, Schmelcher believes that this is currently easier than for phages. Protein-based drugs are well established, and the authorisation process is defined. By contrast, phages which multiply inside the body are obviously considered more difficult to control. In any case, most countries are lacking a legal framework for this therapy, which has been known for over a century. It has mainly been practised in Georgia, and for several years now also in Belgium. In Switzerland, phages may only be used in exceptional cases if approved antibiotics fail.

Schmelcher sees no reason to pit endolysins against phages. For certain bacteria with differently structured cell walls, phages are currently better suited, he says, emphasizing that “in light of the antibiotics crisis, we need to further develop both fields and collect clinical data.” Development is mainly being driven by start-ups and SMEs, while large pharmaceutical groups have shown little interest to date. Schmelcher envisages a realistic scenario where endolysins are initially used alongside antibiotics to treat severe infections. “This would buy us valuable time in the fight against resistance,” he says.

Lead image: Adobestock/Vladimir Borovic