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The venom of insects such as wasps and bees is full of compounds that kill bacteria. Unfortunately, many of these compounds are also toxic to humans, making their use as antibiotics impossible.
After systematically investigating the antimicrobial properties of a toxin that is normally found in a South American wasp, MIT researchers have now created peptide variants that are effective against bacteria but non-toxic to humans. human cells, reported Phys.
In a study of mice, the researchers found that their most potent peptide could completely eliminate Pseudomonas aeruginosa, a strain of bacteria that causes respiratory and other infections and is resistant to most antibiotics.
"We have transformed a toxic molecule into a viable molecule to treat infections," says Cesar de la Fuente-Nunez, MIT postdoc. "By systematically analyzing the structure and function of these peptides, we were able to adjust their properties and activity."
De la Fuente-Nunez is one of the lead authors of this article, published in the December 7 issue of Nature Communications Biology. Timothy Lu, associate professor of MIT in Electrical Engineering, Computer Science and Biological Engineering, and Vani Oliveira, associate professor at the Federal University of ABC in Brazil, are also senior authors. The main author of the document is Marcelo Der Torossian Torres, former visiting student at MIT.
Venomous variants
As part of their immune defenses, many organisms, including humans, produce peptides that kill bacteria. To help fight the emergence of antibiotic-resistant bacteria, many scientists have been trying to adapt these peptides as potential new drugs.
The peptide on which Fuente-Nunez and his colleagues concentrated in this study was isolated from a wasp known as Polybia paulista. This peptide is small enough (12 amino acids) for researchers to think that it would be possible to create some of its variants and test them to see if they could become more effective against microbes and less harmful to humans.
"It's a peptide small enough that you can try to mutate as much amino acid residues as possible in order to understand how each component contributes to the activity and toxicity of antimicrobials." explained Mr. de la Fuente-Nunez.
Like many other antimicrobial peptides, it is thought that this peptide derived from venom kills microbes by disrupting bacterial cell membranes. The peptide has an alpha-helical structure, known to interact strongly with cell membranes.
During the first phase of their study, the researchers created a few dozen variants of the original peptide and then measured the impact of these modifications on the helical structure of the peptides and on their hydrophobic character. which also makes it possible to determine the degree of interaction of the peptides with the membranes. They then tested these peptides against seven strains of bacteria and two of fungi, which correlated their structure and physicochemical properties with their antimicrobial potency.
Based on the structure-function relationships that they identified, the researchers then designed a few tens of additional peptides for further testing. They were able to identify the optimal percentages of hydrophobic amino acids and positively charged amino acids. They also identified a group of amino acids where any modification would alter the overall function of the molecule.
Fight the infection
To measure the toxicity of the peptides, the researchers exposed them to human embryonic kidney cells grown in a lab box. They selected the most promising compounds to test in mice infected with Pseudomonas aeruginosa, a common source of respiratory and urinary tract infections, and found that many of the peptides could reduce infection. Any of them, administered in high doses, could eliminate it completely.
"After four days, this compound can completely eliminate the infection, which was quite surprising and exciting, as we usually do not see it with other experimental antimicrobials or other antibiotics we tested. in the past with this mouse model in particular "de la Fuente-Nunez said.
Researchers have begun to create additional variants that they hope will be able to eliminate infections at lower doses. De la Fuente-Nunez also plans to apply this approach to other types of naturally occurring antimicrobial peptides when it joins the faculty of the University of Pennsylvania. next year.
"I think some of the principles we've learned here can be applied to other similar peptides derived from nature," he said. "Elements such as helicity and hydrophobicity are very important for many of these molecules, and some of the rules we learned here can certainly be extrapolated."
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