Enzyme therapy restores antibiotic effectiveness against drug-resistant meningitis

Combination of endolysin and antibiotics shown to protect all organs, including the brain, in study

Administering an enzyme known as endolysin alongside antibiotics restores the drugs' effectiveness against resistant bacteria and provides protection against infection throughout the body, including the brain, according to a new study using mouse models. The findings could represent a major step forward in the treatment of antibiotic-resistant meningitis.

Antibiotic resistance is considered one of the greatest threats to global health by the World Health Organization. Two major classes of antibiotics – beta-lactams (such as penicillin) and macrolides (such as erythromycin) – are widely used to treat severe infections, including bacterial meningitis. However, increasing resistance to these antibiotics is putting patients at risk of severe or permanent neurological damage, even when they survive the infection.

“There are two major challenges in treating meningitis: the difficulty antibiotics have in crossing the blood–brain barrier and the growing prevalence of resistant bacteria,” said Dr Federico Iovino, principal investigator and associate professor at the Department of Neuroscience, Karolinska Institutet.

“Our results show that by supplementing treatment with endolysins, we can restore antibiotic efficacy, even against resistant strains.”

Endolysins are enzymes derived from bacteriophages – viruses that infect and destroy bacteria. Though already proven effective in veterinary medicine, particularly against mastitis in livestock, their potential in human medicine has remained largely unexplored until now.

In laboratory experiments, the team demonstrated that an endolysin known as cpl-1 protected human cells exposed to Streptococcus pneumoniae, the bacterium responsible for most meningitis cases worldwide. These bacterial strains were resistant to either penicillin or erythromycin. The combination of endolysin with each antibiotic resulted in effective protection of nerve cells.

“The combination protected neurons from infection by highly resistant pneumococcal strains collected from Swedish hospitals,” said Niels Vander Elst, postdoctoral researcher and first author of the study.

“This is significant, as these strains are known to cause meningitis in clinical settings,” he added.

The researchers further tested the treatment in mice infected with penicillin-resistant pneumococci. While penicillin alone proved ineffective, endolysin by itself offered partial protection. Crucially, the combination therapy completely protected the animals and restored the antibiotic's ability to fight the infection.

“Antibiotics take time – often days – to cross the blood–brain barrier, whereas endolysin can reach the brain within hours,” said Dr Iovino.

“That speed is critical because nerve cells begin to suffer damage as soon as the infection sets in. Furthermore, endolysin’s mechanism of action does not allow the bacteria time to develop resistance.”

Dr Iovino’s group now plans to expand their research to test the efficacy of endolysins against other forms of antibiotic-resistant bacteria that cause serious illnesses. Their long-term goal is to develop endolysin-based therapies as adjuncts to existing antibiotics in the clinical treatment of bacterial infections.

“This is the first time we have demonstrated that endolysin is effective against the pathogens responsible for meningitis,” said Dr Iovino. “Our findings also close a major gap in our understanding by confirming that endolysin can cross the blood–brain barrier and help antibiotics overcome resistance.”

The research was funded by the Swedish Research Council, HRH Crown Princess Lovisa’s Association for Paediatric Care, the Magnus Bergvall Foundation, the Åhlén Foundation, the Silent School Foundation, the Wera Ekström Fund for Paediatric Research and the Gun and Bertil Stohne Foundation.

For further reading please visit: 10.1186/s10020-025-01226-1