A team led by scientists at the Perelman School of Medicine at the University of Pennsylvania designed powerful new antimicrobial molecules from toxic proteins found in wasp venom The team hopes to develop the molecules by new drugs that kill bacteria, an important breakthrough given the growing number of antibiotic-resistant bacteria that can cause diseases such as sepsis and tuberculosis
In the study, published today in the Proceedings of the National Academy of Sciences, researchers modified a small, highly toxic protein from a species of common Asian wasp, Vespula lewisii, the Korean yellowjacket wasp The changes improved the molecule’s ability to kill bacterial cells while significantly reducing its ability to harm human cells. In animal models, scientists have shown that this family of new antimicrobial molecules made with these alterations can protect mice against otherwise deadly bacterial infections.
There is an urgent need for new drug treatments for bacterial infections, as many circulating bacterial species have developed resistance to older drugs The US Centers for Disease Control & Prevention has estimated that each year, nearly three millions of Americans are infected with antibiotic-resistant microbes and more than 35,000 die from them Globally, the problem is even worse: sepsis, an often fatal inflammatory syndrome triggered by widespread bacterial infection, has reportedly been rooted in origin of about one in five deaths worldwide as recently as 2017
New antibiotics are urgently needed to treat the ever-growing number of drug-resistant infections, and venoms are an untapped source of potential new drugs We believe molecules derived from venom such as the ones we designed in this study are going to be a valuable source of new antibiotics «
César de la Fuente, PhD, lead author of the study, presidential assistant professor of psychiatry, microbiology and bioengineering at Penn
De la Fuente and his team started with a small protein, or « peptide, » called mastoparan-L, a key ingredient in wasp venom Vespula lewisii Venom containing Mastoparan-L is generally not harmful to people. humans in small doses delivered by wasp stings, but it is quite toxic It destroys red blood cells and triggers a type of allergic / inflammatory reaction which in sensitive people can lead to a fatal syndrome called anaphylaxis – in which high blood pressure fall and breathing becomes difficult or impossible
Mastoparan-L (mast-L) is also known for its moderate toxicity to bacterial species, making it a potential starting point for the design of new antibiotics But there are still unknowns, including how to improve its properties antibacterials and how to make it safe for humans
The team searched a database of hundreds of known antimicrobial peptides and found a small region, the pentapeptide motif, which was associated with high activity against bacteria The researchers then used this motif to replace a section at one end of mast-L which is said to be the main source of toxicity for human cells
In a series of key experiments, researchers treated mice with mast-MO several hours after infecting them with strains of the bacteria E that would otherwise be fatal and induce sepsis coli or Staphylococcus aureus In each test, the antimicrobial peptide kept 80% of treated mice alive.In contrast, mice treated with mast-L were less likely to survive and had severe toxic side effects when treated with doses higher – doses at which mast-MO caused no obvious toxicity
The potency of mast-MO in these tests also appeared to be comparable to that of existing antibiotics such as gentamicin and imipenem – for which alternatives are needed due to the spread of resistant bacterial strains
De la Fuente and colleagues found evidence in the study that mast-MO kills bacterial cells by making their outer membranes more porous – which may also improve the ability of co-administered antibiotics to penetrate them. cells – and by summoning antimicrobial white blood cells At the same time, mast-MO appears to attenuate the type of harmful immune overreaction that can lead to serious illness in some bacterial infections
Researchers created dozens of mast-MO variants and found several that appeared to have significantly enhanced antimicrobial potency without any toxicity to human cells They hope to develop one or more of these molecules into new antibiotics – and they hope to take a similar approach in the future to turn other poisonous toxins into promising antibiotic candidates.
« The principles and approaches we used in this study can be applied more broadly to better understand the antimicrobial and immunomodulatory properties of peptide molecules, and to harness this understanding to create valuable new treatments, » said de la Fuente
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