Peptides are small protein molecules that control many processes in the human body. Some of them fight invaders such as bacteria and viruses as part of the innate immune system. Lactoferrin is also part of this defense force. Researchers at the University of Graz have now shown how powerful antimicrobial peptides - so-called AMPs - derived from lactoferrin are. And they did so using the E. coli bacterium, which can go from being a harmless intestinal inhabitant to the most common cause of diarrhea and inflammation. Spoiler alert: There is a murder at the end of this story!
On the trail of the killers
In fact, the AMPs made short work of the E. coli bacteria. "Within a few seconds, they had overcome the bacterium's outermost protective envelope and penetrated the cell interior," says Enrico Semeraro, describing the lightning-like assault in which there were no survivors. "What exactly the AMPs do inside the cell, i.e. how they kill the bacteria, remains a mystery for now. Our publication has, like a thriller, a real cliffhanger ending," admits Georg Pabst, "and of course there are the usual suspects."
In fact, what is special about the paper, published in the online journal eLife, is not the comprehensive elucidation of the "E. coli murder." Rather, it's the approach the team took to observe AMPs as they attacked - in real time and simultaneously on length scales that describe bacterial size (micrometers) and molecular structures (nanometers). "Our technique can be applied to other questions about molecular processes in cells. It allows us to find new solutions to certain problems that are otherwise inaccessible," Karl Lohner emphasizes.
Old tried and tested rethought
The "highlight" of the biophysicists' approach: they have used a time-honored method for the structural investigation of non-crystalline materials - known as small-angle scattering - for the first time to accurately "screen" bacteria. "Small-angle scattering gives us an incredible amount of data on the nature of molecular structures in these organisms. This was both an opportunity and a challenge. We had to painstakingly filter out what was relevant to us by combining mathematics, physics, chemistry and molecular biology," explains Enrico Semeraro.
The effort was doubly worthwhile: On the one hand, the scientists have thus brought a new application of small-angle scattering onto the scene. On the other hand, the findings about the rapid demise of E. coli bacteria could also improve the design of novel antibiotics in the future.
The end of the key and lock
At the moment, these work according to a "lock and key" principle, i.e. they are "set" precisely to the bacterium to be combated. As researchers discover more about how AMPs work, they could be equipped with specific instructions as "hit men" and thus play tricks on bacteria that are becoming increasingly resistant to conventional methods. "This is still a dream of the future, but we still believe that our approach is right and important for such considerations," Semeraro is convinced.
Think outside the box
Breaking out of tried-and-tested thought patterns - that, by the way, is also what brought the native Italian to Graz. Chance brought Enrico Semeraro and Georg Pabst together at a conference in Dresden. Small-angle scattering and E. coli quickly became a topic. "And then it 'clicked,'" Pabst smiles. Seven years later, the two colleagues are at the Institute of Molecular Biosciences at the University of Graz and have successfully implemented the idea by means of an interdisciplinary collaboration within the Field of Excellence BioHealth. Their current publication shows how important creativity, unconventional ideas and cross-border approaches are also in natural science research.
Publication: Semeraro et al. "Lactoferricins impair the cytosolic membrane of Escherichia coli within a few seconds and accumulate inside the cell." eLife. DOI: https://doi.org/10.7554/eLife.72850