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 and at the same time increasing their effectiveness against bacteria. The candidate for the development of new antibiotics works by breaking the microbes’ shell and calling immune cells to fight the pathogens, the researchers report.
“You have become infected with a multi-resistant germ” is a feared diagnosis more and more often. Many bacterial pathogens can no longer be killed by common antibiotics, because they have developed genetic characteristics that protect them from the effects of these substances. The so-called hospital germ MRSA – a multi-resistant strain of the bacterium Staphylococcus aureus – is particularly notorious in this context. If the antibiotic no longer works, an infection with this germ can lead to life-threatening blood poisoning – sepsis. This is a huge problem in medicine: it is estimated that around one in five deaths worldwide can be traced back to such uncontrolled and body-wide infections.
Wasp venom in sight
It is therefore clear that there is an enormous need for alternative active ingredients to the previous antibiotics. Traditionally, many of the active ingredients come from fungal organisms, but the search for sources for novel substances has now expanded to include many living things. In this context, the researchers led by César de la Fuente from the University of Pennsylvania in Philadelphia are investigating the potential of active ingredients from animal poisons. Her focus was on the peptide Mastoparan-L, which forms the central active ingredient of the venom of the wasp species Vespula lewisii. It had shown an antibacterial effect in preliminary studies and was therefore the focus of the researchers. But as everyone who has 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 life-threatening anaphylactic shock in susceptible individuals. As part of their study, the scientists have therefore explored the extent to which the desired and problematic aspects of the molecule can be optimized through targeted changes to its characteristics.
To do this, they first carried out a comprehensive database search for the known antibacterial peptides. They identified an apparently typical structural feature of these substances, which suggested a function in connection with the antibacterial effect: the so-called pentapeptide motif. They then modified the Mastoparan-L from the wasp venom using protein design techniques: They replaced the section that they believed to be the cause of the toxicity for human cells with the previously identified pentapeptide motif. There was therefore hope for a double success: The modified peptide Mast-MO could have increased effectiveness against microbes and at the same time be harmless for use in humans.
Promising test results
To explore this potential, the researchers carried out experiments on mice. The animals were infected with sepsis-causing strains of the bacterium E. coli or Staphylococcus aureus, which is usually fatal. One group of the animals then received a dose of the newly developed peptide Mast-MO, while another group received the wasp’s natural active ingredient. It turned out that while most of the comparison animals succumbed to sepsis, the fattening MO was able to keep 80 percent of the treated mice alive. There were also no toxic effects of the natural substance. The scientists report that the effect could be compared with that of antibiotics such as gentamicin and imipenem, for which alternatives are required due to the spread of resistant bacterial strains.
Through further research, they were able to gain insights into what the effect of the Mast-MO is based on. The optimized peptide kills bacterial cells by making their outer membranes porous. This could also be helpful in the context of a combination treatment, say the researchers: additionally administered active ingredients could penetrate the pathogens better in this way. They also found evidence that the active ingredient leads to an increased concentration of immune cells at infection sites. At the same time, Mast-MO appears to dampen the type of harmful immune overreaction that can lead to severe courses in some bacterial infections, the scientists report.
In the meantime, they have already created dozens of variants of the peptide and have found several that can apparently significantly increase the antimicrobial effectiveness without toxicity to human cells. So they now hope that one or more of these substances can be used to develop new antibiotics. In addition, their concept could also be used with other poisons to turn them into antibiotic candidates. “The principles and approaches that we used in this study can be applied more broadly to better understand the antimicrobial and immunomodulatory properties of peptide molecules and to use that understanding to develop new treatment options,” says de la Fuente.
Source: University of Pennsylvania, Article: PNAS, doi: 10.1073 / pnas.2012379117