Pseudoscorpions are small arachnids that look like a scorpions but lack a tail and stinger. They’re “fake” scorpions, typically only a few millimeters in length. Despite their lack of a stinger, they still have venom — it’s in their pincers, which they use to immobilize prey. This venom is used to hunt pests like mites and lice. Soon, it could be used to hunt methicillin-resistant Staphylococcus aureus (MRSA).

Pseudoscorpions primarily live in Central Europe, where they usually go unnoticed because of their small size. This size (1 to 7 millimeters) also makes it difficult to capture and analyze them and their venom. Despite having around 3,000 species, pseudoscorpions are rarely analyzed as venomous creatures. Researchers in Hesse, Germany, took on that challenge.

“Animal venoms are a veritable treasure trove of potential drug candidates, but only a small proportion have been investigated so far,” says study leader Dr. Tim Lüddecke, head of the junior research group Animal Venomics at Fraunhofer IME-BR and Justus Liebig University Giessen and member of the LOEWE Center TBG.

“In my group, we have developed modern systems biology and biotechnological methods to study the very small venomous animals that are difficult to analyze. In particular, we focus on arachnids. They are the master chemists of venomous animals — Their venoms are particularly complex and pharmacologically promising.”

The team not only analyzed but also synthesized all the toxins produced by the book scorpion (Chelifer cancroides). They wanted to see what types of organisms these toxins would be good against, and they found that they were excellent against MRSA.

The good, the bad, and the venomous

MRSA has become a big global problem in hospital settings. It’s already a superbug responsible for numerous hospital-acquired infections. And Staphylococci (Staph) themselves are rather common bacteria that can colonize the skin and mucous membranes. What makes the MRSA variants so dangerous is that they’re resistant to methicillin, a drug commonly used to eliminate staph. This means that even during or after surgery, it’s difficult for doctors to kill all the MRSA around and ensure that there’s no infection in the patient.

MRSA has emerged as one of the most pressing global health problems and the prospect of a bacterium we simply can’t kill is horrifying. This is why researchers are looking for solutions, even in exotic places like pseudoscorpions.

The researchers focused on a family of toxins known as checacins. Checacins work by disrupting bacterial cell membranes. Their cationic (positively charged) nature allows them to bind to the negatively charged components of bacterial cell walls. This leads to membrane destabilization and cell death. This mode of action is particularly effective against bacteria that have developed resistance to other antibiotics, which often target specific bacterial enzymes or proteins. By attacking the fundamental structure of bacterial cells, checacins offer a different approach that could circumvent existing resistance mechanisms.

Dr. Pelin Erkoc, one of the study authors, says this pseudoscorpion toxin is very effective against MRSA, but there’s a catch. It’s also toxic to human cells.

“Our data show that the checacins unfortunately also have a certain toxicity for human cells and could possibly cause inflammatory reactions themselves.”

“Therefore, we still need to optimize their structure and thus their effect using biotechnological processes, as is the case with other active substances,” explains Erkoc.

It’s one of mankind’s biggest looming threats

The stakes could not be higher, the researchers add. Antibiotic resistance is set to become one of mankind’s most pressing problems, and MRSA is a key concern. In addition to their antibacterial properties, some checacins also exhibit antifungal activity, making them versatile agents in the fight against microbial infections. The study found that checacins inhibited the growth of Candida albicans, a common cause of fungal infections in humans.

“However, the potential of these compounds is already clear. It is predicted that antibiotic-resistant infections could become the leading cause of disease-related death worldwide in the coming decades. It is therefore important to look for new solutions with unusual ideas,” adds Dr. Michael Marner, postdoctoral researcher at Fraunhofer IME-BR and co-author of the study.

Researchers could attempt to tweak this toxin and keep its anti-MRSA properties while making it safe for humans — which is already in the works. Another approach is to keep scouting venomous creatures and look at the venom of other species. Hopefully more promising compounds can be found — and this is also something we should focus on, the researchers say.

Venomics for the future

The study of checacins is part of a broader field known as venomics. The field aims to catalog and understand the vast array of bioactive compounds found in animal venoms. Advances in mass spectrometry, next-generation sequencing, and biotechnology have made it possible to explore venom from even the smallest creatures. This holistic approach not only expands the pool of potential drug candidates but also sheds light on the complex evolutionary processes that have shaped these potent natural weapons.

Ultimately, there seems to be great untapped potential in venomics, and researchers say we’d be wise to harvest it.

“Our new results on the checacins show how worthwhile it is to take a closer look at the unknown universe of venoms of small creepy-crawlies,” Lüddecke concludes.

Pelin Erkoc et al, Determining the pharmacological potential and biological role of linear pseudoscorpion toxins via functional profiling, iScience (2024). DOI: 10.1016/j.isci.2024.110209