Insect venom such as wasps and bees is full of compounds that can kill bacteria. Unfortunately, many of these compounds are also toxic to humans, making it impossible to use them as antibiotic drugs.
After conducting a systematic study of the antimicrobial properties of a toxin normally present in a South American wasp, MIT researchers have now created peptide variants that are potent against bacteria but non-toxic to human cells.
In a study of mice, the researchers found that their stronger peptide could completely eliminate Pseudomonas aeruginosa, a strain of bacteria that causes respiratory and other infections and is resistant to most antibiotics.
"We have re-proposed a toxic molecule in one that is a vital molecule for treating infections," says Cesar de la Fuente-Nunez, a MIT postdoc. "By systematically analyzing the structure and function of these peptides, we have been able to fine-tune their properties and activities."
De la Fuente-Nunez is one of the senior authors of the newspaper, which appears in the December 7 issue of the journal Nature Communications Biology. Timothy Lu, an associate professor of electrical engineering and computer science and biological engineering at MIT, and Vani Oliveira, an associate professor at the Federal University of ABC in Brazil, are also senior authors. The main author of the paper is Marcelo Der Torossian Torres, a former student visiting MIT.
As part of their immune defenses, many organisms, including humans, produce peptides that can kill bacteria. To help fight the emergence of antibiotic-resistant bacteria, many scientists have tried to adapt these peptides as potential new drugs.
The peptide that de la Fuente-Nunez and his colleagues focused on this study was isolated from a wasp known as Polybia paulista. This peptide is small enough – only 12 amino acids – that the researchers thought was feasible to create some variants of the peptide and test them to see if they could become more powerful against microbes and less harmful to humans.
"It is a peptide small enough to try to change as many amino acid residues as possible to try to understand how each individual block contributes to antimicrobial activity and toxicity," says de la Fuente-Nunez.
Like many other antimicrobial peptides, this poison-derived peptide is believed to kill microbes by destroying bacterial cell membranes. The peptide has a helical alpha structure, which is known to interact strongly with cell membranes.
In the first phase of their study, the researchers created dozens of variants of the original peptide and then measured how these changes affected the helical structure of the peptides and their hydrophobicity, which also helps determine how much the peptides interact with. the membranes. They then tested these peptides against seven bacterial and two fungi strains, making it possible to correlate their structure and physico-chemical properties with their antimicrobial efficacy.
Based on the structure-function relationships they identified, the researchers then designed another dozen peptides for further testing. They were able to identify optimal percentages of positively charged hydrophobic amino acids and amino acids, and also identified a cluster of amino acids where any changes would compromise the overall function of the molecule.
Fight the infection
To measure the toxicity of peptides, the researchers exposed them to human embryonic kidney cells grown in a laboratory dish. They selected the most promising compounds to be tested in infected mice Pseudomonas aeruginosa, a common source of respiratory tract and urinary tract infections, and found that many of the peptides could reduce infection. One of these, given at a high dose, could completely eliminate it.
"After four days, that compound can completely eradicate the infection, and it was quite surprising and exciting because we do not usually see it with other experimental antimicrobials or other antibiotics that we have tested in the past with this particular" de la "mouse model. Fuente-Nunez says.
Researchers have begun to create more variants that they hope will eliminate infections at lower doses. De la Fuente-Nunez also plans to apply this approach to other types of natural antimicrobial peptides when joining the faculty of the University of Pennsylvania next year.
"I think some of the principles we have learned here can be applicable to other similar peptides derived from nature," he says. "Things like elasticity and hydrophobicity are very important for many of these molecules, and some of the rules we've learned here can definitely be extrapolated."
The screen of human proteins reveals some with antimicrobial power
Marcelo D. T. Torres et al. The exploration guided by the structure function of the polycyclic antimicrobial peptide identifies the determinants of the activity and generates synthetic therapeutic candidates, Biology of communications (2018). DOI: 10.1038 / s42003-018-0224-2