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Penn Medicine scientists engineer bacteria-killing molecules from wasp venom

PHILADELPHIA–A team led by scientists in the Perelman School of Medicine at the University of Pennsylvania has engineered powerful new antimicrobial molecules from toxic proteins found in wasp venom. The team hopes to develop the molecules into new bacteria-killing drugs, an important advancement considering increasing numbers of antibiotic-resistant bacteria which can cause illness such as sepsis and tuberculosis.

In the study, published today in the Proceedings of the National Academy of Sciences, 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.

There is an urgent need for new drug treatments for bacterial infections, as many circulating bacterial species have developed a resistance to older drugs. The U.S. Centers for Disease Control & Prevention has estimated that each year nearly three million Americans are infected with antibiotic-resistant microbes and more than 35,000 die of them. Globally the problem is even worse: Sepsis, an often-fatal inflammatory syndrome triggered by extensive bacterial infection, is thought to have accounted for about one in five deaths around the world as recently as 2017.

“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,” said study senior author César de la Fuente, PhD, a Presidential Assistant Professor in 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 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 destroys red blood cells, and triggers a type of allergic/inflammatory reaction that in susceptible individuals can lead to a fatal syndrome called anaphylaxis–in which blood pressure drops and breathing becomes difficult or impossible.

Mastoparan-L (mast-L) also is known for its moderate toxicity to bacterial species, making it a potential starting point for engineering new antibiotics. But there are still some unknowns, including how to enhance its anti-bacterial properties, 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 so-called pentapeptide motif, that was associated with strong activity against bacteria. The researchers then 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.

In a key set of experiments, the researchers treated mice with mast-MO several hours after infecting them with otherwise lethal, sepsis-inducing strains of the bacteria E. coli or Staphylococcus aureus.

Penn Medicine researchers discover a rare genetic form of dementia

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IMAGE: Abnormal neurofibrillary tangles (NFTs) — a buildup of tau protein in parts of the brain — helped Edward Lee, MD, PhD, an assistant professor of Pathology and Laboratory Medicine, and…
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Credit: Edward Lee

PHILADELPHIA — A new, rare genetic form of dementia has been discovered by a team of Penn Medicine researchers. This discovery also sheds light on a new pathway that leads to protein build up in the brain — which causes this newly discovered disease, as well as related neurodegenerative diseases like Alzheimer’s Disease — that could be targeted for new therapies. The study was published today in Science.

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by a buildup of proteins, called tau proteins, in certain parts of the brain. Following an examination of human brain tissue samples from a deceased donor with an unknown neurodegenerative disease, researchers discovered a novel mutation in the Valosin-containing protein (VCP) gene in the brain, a buildup of tau proteins in areas that were degenerating, and neurons with empty holes in them, called vacuoles. The team named the newly discovered disease Vacuolar Tauopathy (VT)–a neurodegenerative disease now characterized by the accumulation of neuronal vacuoles and tau protein aggregates.

“Within a cell, you have proteins coming together, and you need a process to also be able to pull them apart, because otherwise everything kind of gets gummed up and doesn’t work. VCP is often involved in those cases where it finds proteins in an aggregate and pulls them apart,” Edward Lee, MD, PhD, an assistant professor of Pathology and Laboratory Medicine in the Perelman School of Medicine at the University of Pennsylvania. “We think that the mutation impairs the proteins’ normal ability to break aggregates apart.”

The researchers noted that the tau protein they observed building up looked very similar to the tau protein aggregates seen in Alzheimer’s disease. With these similarities, they aimed to uncover how this VCP mutation is causing this new disease — to aid in finding treatments for this disease and others. Rare genetic causes of diseases can very often offer insight into more prevalent ones.

The researchers first examined the proteins themselves, in addition to studying cells and an animal model, and found that the tau protein buildup is, in fact, due to the VCP mutation.

“What we found in this study is a pattern we’ve never seen before, together with a mutation that’s never been described before,” Lee said. “Given that this mutation inhibits VCP activity, that suggest the converse might be true — that if you’re able to boost VCP activity, that could help break up the protein aggregates. And if that’s true, we may be able to break up tau aggregates not only for this extremely rare disease, but for Alzheimer’s disease and other diseases associated with tau protein aggregation.”

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Lee led this work with first author, Nabil Darwich, MD/PhD student in the Neuroscience Graduate Group at Penn.

These findings describe a new biologic function of VCP, define a