According to the Centers for Disease Control and Prevention (CDC), antibiotic resistance is one of the biggest public health challenges of our time. Each year in the United States, at least 2.8 million people get an antibiotic-resistant infection, and more than 35,000 people die. Now, researchers from the Perelman School of Medicine at the University of Pennsylvania (Penn) report they have engineered powerful new antimicrobial molecules from toxic proteins found in wasp venom. The molecules may one day lead to new bacteria-killing drugs, needed to combat antibiotic-resistant illnesses such as sepsis and tuberculosis.

Their findings, “Repurposing a peptide toxin from wasp venom into antiinfectives with dual antimicrobial and immunomodulatory properties,” were recently published in PNAS.

The researchers altered a highly toxic small protein from a common Asian wasp species, Vespula lewisii, the Korean yellow-jacket wasp. The alterations enhanced the molecule’s ability to kill bacterial cells while greatly reducing its ability to harm human cells. In animal models, the scientists showed that this family of new antimicrobial molecules made with these alterations could protect mice from otherwise lethal bacterial infections.

“Novel antibiotics are urgently needed to combat multidrug-resistant pathogens. Venoms represent previously untapped sources of novel drugs,” the researchers wrote. “Here we repurposed mastoparan-L, the toxic active principle derived from the venom of the wasp Vespula lewisii, into synthetic antimicrobials. We engineered within its N terminus a motif conserved among natural peptides with potent immunomodulatory and antimicrobial activities.”

“New antibiotics are urgently needed to treat the ever-increasing number of drug-resistant infections, and venoms are an untapped source of novel potential drugs. We think that venom-derived molecules such as the ones we engineered in this study are going to be a valuable source of new antibiotics,” explained study senior author, César de la Fuente, PhD, a presidential assistant professor in psychiatry, microbiology, and bioengineering at Penn.

Venoms wouldn’t normally seem like a potential healer, but the venom of various animals and insects, such as scorpions, rattlesnakes, and wasps have been proven to show as promising drug candidates. The toxins in venoms have been honed to target highly specific components of their prey’s vital bodily functions. However, those functions are what make them useful. Venoms from bees, wasps, and scorpions have been used to target HIV, cancer, blood clotting, diabetes, and more.

The researchers started with a peptide, called mastoparan-L, a key ingredient in the venom of Vespula lewisii wasps. Mastoparan-L-containing venom is usually not dangerous to humans in the small doses delivered by wasp stings, but it is quite toxic. It can destroy red blood cells, and trigger a type of inflammatory reaction that in susceptible individuals can lead to anaphylaxis.

The researchers searched a database of hundreds of known antimicrobial peptides and found a small region, the so-called pentapeptide motif, that was associated with strong activity against bacteria. Then they used this motif to replace a section at one end of mast-L that is thought to be the chief source of toxicity to human cells; resulting in a new molecule the team called mastoparan-MO (mast-MO)

Next, they tested the new molecule in mice infected with lethal levels of E. coli. Eighty percent of the treated animals survived, while those that received just the natural mast-L peptide were far less likely to survive. Mast-MO was also able to be safely administered at higher doses, while mast-L invoked severe side effects at the same level.

Looking towards the future, the researchers hope to develop one or more of these molecules and other venom toxins into new promising antibiotic candidates.

“The principles and approaches we used in this study can be applied more broadly to better understand the antimicrobial and immune-modulating properties of peptide molecules, and to harness that understanding to make valuable new treatments,” de la Fuente concluded.

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