If immunotherapy -- the harnessing of the body's immune system -- can destroy cancer cells, as has been demonstrated, why not try to trigger the body's immune system to battle deadly bacteria? That question drives Marcos Pires's pursuit of what he calls bacterial immunotherapy or immunobiotics -- using the human immune system's powerful mechanisms of preventing entry and colonization of pathogens to defeat the deadliest, antibiotic-resistant bacteria. Pires and his research team at Lehigh University, where Pires is an Associate Professor in the Department of Chemistry, have previously demonstrated a successful method of labeling the surface of Gram-positive bacteria with antigenic epitopes -- the part of a foreign substance that is recognized by the immune system -- and then triggering the recruitment of endogenous antibodies.
However, according to Pires, that method was ineffective against Gram-negative bacteria, which have an extra layer of protection around themselves. Gram-negative bacteria -- which includes Pseudomonas aeruginosa , associated with serious illnesses such as pneumonia and sepsis, and the food-borne Escherichia coli E. These bacteria continually evolve, rendering current antibiotics powerless -- and the pipeline for new antibiotic drugs is drying up.
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Now, Pires and his team have designed a strategy aimed at tagging Gram-negative bacteria for destruction via small molecule conjugates they have created that specifically home to bacterial cell surfaces and trigger an immune response. The researchers describe their work in a paper to be published in Cell Chemical Biology called: "Synthetic Immunotherapeutics Against Gram-negative Pathogens.
The small-molecule conjugates they have created were assembled using polymyxin B PMB -- an antibiotic that inherently attaches to the surface of Gram-negative pathogens -- and antigenic epitopes that recruit antibodies found in human serum. It just so happens that it destroys bacteria by landing on its surface. We modified colistin with an agent that attracts antibodies onto the surface of the bacteria and built a compound that both directly kills bacteria and at the same time induces an immune-response.
Their compound targets pathogenic bacteria in two distinct ways to generate a very promising lead in immunotherapeutic agents for advanced testing.
The team conducted experiments using a panel of Gram-negative pathogens, including E. They treated the bacteria with their compounds in real human serum and observed a significant decrease in the number of live bacteria.
This is a clear indication, says Pires, that the method is working by successfully harnessing the immune system to target this dangerous disease-causing bacteria. The research brought Pires's group into contact with Lehigh colleague, Wonpil Im, the Presidential Endowed Chair in Health and Professor of Biological Sciences and Bioengineering, in a synergistic, interdisciplinary collaboration.
Im, who is a co-author on the paper, uses computational biophysics to learn how antibiotics permeate bacterial membranes and target bacteria for destruction. His research group has developed CHARMM-GUI, an open-access research program that simulates complex biomolecular systems more simply and more precisely than previously possible.
The tool is becoming increasingly valuable as more bacteria develop resistance to antibiotics. In the paper, the authors write: "In conclusion, we have designed and synthesized a unique class of immunotherapeutic agents that exploits the lipid A binding scaffold of polymyxins to decorate the surface of Gram-negative bacteria with haptens. We showed that the most potent members of this panel trigger the opsonization of E.
Most significantly, the lead agent induced CDC-based killing of E.
Immunotherapy for Infectious Diseases Conference (students and postdocs), November 12-14, 2018
Featuring speakers Dr. Yvonne Perrie and Dr. Richner earned his doctoral degree from the University of California at Berkeley under the mentorship of Dr. Britt Glaunsinger. He performed his post-doctoral studies at Washington University in St. Louis with Dr. Michael Diamond studying viral immunology and vaccine development.
Infection, Inflammation and Immunotherapy
In this setting he developed, in collaboration with Moderna, a Zika virus vaccine with the novel mRNA-lipid nanoparticle gene therapy platform. Abstract: The emergence of Zika virus ZIKV infection has prompted a global effort to develop safe and effective vaccines. Vaccinated dams challenged with a heterologous ZIKV strain showed markedly diminished levels of viral RNA in maternal, placental, and fetal tissues, which resulted in protection against placental damage and fetal demise.