Hope in the fight against antibiotic-resistant germs: Researchers have produced an active ingredient from a component of wasp venom that could fight bacterial infections in animal experiments.
They have succeeded in eliminating the problematic aspects of the toxic substance for humans while at the same time increasing its effectiveness against bacteria.
The candidate for the development of new antibiotics works by breaking open the microbes’ shells and inducing immune cells to fight the pathogens, the researchers report.
“You have become infected with a multi-resistant germ” is a dreaded diagnosis with increasing frequency. Standard antibiotics can no longer kill many bacterial pathogens because pathogens have developed genetic traits that protect them from these substances’ effects.
One particularly notorious example in this context is the so-called hospital germ MRSA – a multi-resistant strain of the bacterium Staphylococcus aureus. If an antibiotic is no longer effective, an infection with this germ can lead to life-threatening blood poisoning – sepsis.
Germs like MRSA are a huge problem in medicine: it is estimated that around one in five deaths worldwide is due to such uncontrolled, body-wide infections.
Wasp venom as medicine
Thus it is clear: The need for alternative active substances that replace the existing antibiotics is enormous. Traditionally, many of the active ingredients originate from fungal organisms, but in the meantime the search for sources of novel substances has been extended to many living organisms.
In this context, the researchers around César de la Fuente from the University of Pennsylvania in Philadelphia are working on the potential of active ingredients from animal toxins. They focused on the peptide mastoparan-L, which is the central active ingredient of the venom of the wasp species Vespula lewisii.
It had shown an antibacterial effect in preliminary studies and therefore became the focus of the researchers. But as anyone who has ever been stung by a wasp knows, the toxins of the insects are also problematic for us.
As the researchers explain, the natural mastoparan L destroys red blood cells and triggers inflammatory reactions that can lead to a life-threatening anaphylactic shock in susceptible individuals.
Within the framework of their study, scientists explored to what extent the desired and problematic aspects of the molecule can be optimized by targeted changes to its characteristics.
To this end, they first conducted a comprehensive database search on the known antibacterial peptides.
Thus, they identified an apparently typical structural feature of these substances, which suggested a function related to their antibacterial effect: the so-called pentapeptide motif.
Using protein design techniques, the scientists systematically modified the mastoparan-L from the wasp venom: they replaced the section they believed to be the cause of toxicity to human cells with the previously identified pentapeptide motif.
Thus, there was hope for a double success: the modified peptide MastMO should have increased potency against microbes and at the same time be safe for use in humans.
Promising test results
To investigate this potential, researchers conducted experiments on mice. The animals were infected with strains causing septicaemia of E. coli or Staphylococcus aureus bacteria, which are usually fatal.
One group of animals then received a dose of the newly developed MO peptide mast. At the same time, another group received the natural active ingredient of the wasp.
It was shown that while most comparison animals succumbed to septicaemia, the MO of the mast kept 80 percent of the treated rats alive. The toxic effects of the natural substance did not occur either.
Therefore, the effect could be compared with that of antibiotics such as gentamicin and imipenem, for which alternatives are needed due to the spread of resistant bacterial strains, the scientists reported.
Through further research, they could also obtain knowledge on what the effect of the mast MO is based on. Optimized peptide kills bacterial cells by making their outer membranes porous.
This could also be useful in the context of a combined treatment, researchers say:
“The active substances administered could thus penetrate pathogens more effectively.”
They also found indications that the active substance leads to a higher concentration of immune cells at the infection sites. Simultaneously, Mast-MO seems to cushion the type of excessive harmful immune reaction that can lead to severe courses of some bacterial infections, the scientists report.
Scientists have now generated dozens of peptide variants. They have found several that appear to significantly increase antimicrobial efficacy without toxicity to human cells.
They now hope that new antibiotics can be developed from one or more of these substances. Also, their concept could be transferred to other toxins to make them candidates for antibiotics.
“The principles and approaches we have used in this study can be applied on a broader scale to better understand the antimicrobial and immunomodulatory properties of peptide molecules and to use this understanding to develop new treatments,” de la Fuente said.
Source: University of Pennsylvania, professional article: PNAS, DOI: 10.1073/pnas.2012379117