Anti-bacterial drug resistance is a growing predicament across the globe. The World Health Organization (WHO) reports that a growing number of infections, including tuberculosis, pneumonia, gonorrhea, and salmonellosis, are becoming more challenging to treat as the antibiotics that are used to treat them become less effective.
Now, a team of scientists in the Perelman School of Medicine at the University of Pennsylvania has engineered potent novel anti-microbial molecules from toxic proteins found in wasp venom. The researchers believe that the discovery holds promise in fighting the increasing number of antibiotic-resistant bacteria, that cause serious illness.
Today, there is an urgent need for new drug treatments for bacterial infections since many bacterial species spreading has developed a resistance to older drugs. The U.S. Centers for Disease Control and Prevention (CDC) also reports that in the country, an estimated three million people are infected with antibiotic-resistant microbes, while more than 35,000 people die of them.
Across the globe, sepsis, which is an inflammatory syndrome caused by an extensive bacterial infection, accounts for about one in five deaths in 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," Dr. César de la Fuente, a Presidential Assistant Professor in Psychiatry, Microbiology, and Bioengineering at the University of Pennsylvania, said.
Venoms represent previously untapped sources of novel drugs. In the study, published in the Proceedings of the National Academy of Sciences, the researchers aimed to determine if the peptide derived from venom can be converted into potent microbials capable of resolving potentially fatal infections in mice.
To arrive at the study findings, the researchers repurposed mastoparan-L, the toxic active principle derived from wasp venom, into a synthetic microbial. The team also engineered it and produced a peptide called mast-MO, which showed more robust anti-bacterial properties in both in vitro and in vivo studies.
Mast-L is also popular for its moderate toxicity to bacterial species, making it a promising starting point for engineering new anti-bacterials.
The team searcher for a database of hundreds of known anti-microbial peptides. They discovered a small region, dubbed as a pentapeptide motif, which was tied to a robust activity against bacteria. From there, the researchers used this motif to replace a part of the mast-L, which is the alleged source of its toxicity to human cells.
Mice models were treated with the new molecule, mast-MO, many hours after being infected with sepsis-inducing strains of Escherichia coli (E. coli) or Staphylococcus aureus.
Experiment findings showed that in each test, the mast-MO kept 80 percent of the treated mice alive. In comparison, mice treated with mast-L were less likely to survive the infection. Further, the latter group experienced severe toxic side-effects when treated with higher doses. In these higher doses, the mast-MO caused no toxicity.
The mast-MO produces an anti-bacterial response by destabilizing the bacterial outer membrane while producing immunomodulatory properties via boosting leukocyte migration to the site of the infection. Also, it acts by suppressing pro-inflammatory factors, which is vital to allow the infection to clear.
"We leverage a sequential rational design strategy to convert a highly toxic peptide derived from wasp venom into nontoxic synthetic derivatives with drug-like properties and anti-infective activity in preclinical animal models," the team explained.
Further, mast-MO acted as a potentiator of conventional antibiotics, which can be used in future applications of the molecule as an adjuvant, a pharmacological or immunological agent that improves the immune response of a vaccine. It can be added to a vaccine to boost the immune response to generate more antibodies for more extended periods.
The researchers also noted that Mast-MO therapy had caused a decrease in pro-inflammatory cytokines IL-12, IL-6, and TNF- α at the infection site in animal models. Overall, the molecule has dual anti-microbial and immunomodulatory actions, including directly killing bacteria and enhance host immune responses to clear infections.
The study shows promise in future drug and vaccine development, which is crucial in the battle against drug-resistant pathogens.
"The principles and approaches we used in this study can be applied more broadly to better understand the anti-microbial and immune-modulating properties of peptide molecules, and to harness that understanding to make valuable new treatments," de la Fuente said.