A research team led by the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID) has developed a treatment strategy that could help combat the use of anthrax in bioterrorism and could also lead to new treatments for other bacterial infections.
The USAMRIID researchers worked with colleagues from the U.S. Naval Research Laboratories, the University of Washington and the University of California at Davis to demonstrate that modifying an enzyme produced by the bacterium that causes anthrax can protect mice from infection with the deadly disease. The findings were published December 8 by Science Translational Medicine.
Bacillus anthracis, the bacterium that causes anthrax, is recognized as one of the most significant bioterrorism threats, as well as a public health challenge in many parts of the world. Three main components allow it to cause disease—lethal toxin, edema toxin, and capsule. In this study, the researchers developed a method to degrade the capsule surrounding the bacterium, allowing it to be ingested and destroyed by the white blood cells—thus reducing the likelihood of infection.
Public health officials have become increasingly concerned about strains of anthrax that appear to be resistant to treatment with known antibiotics, according to Arthur M. Friedlander, MD, the paper’s senior author. Enzymes known as capsular depolymerases (CapD), which are naturally produced by several classes of bacteria, have emerged as a potential new line of antivirulence agents that do not rely on the use of antibiotic drugs.
“Identification of the capsule depolymerase enzyme within the anthrax bacillus led us to attempt to use that enzyme to remove the capsule,” Friedlander said. “When this proved successful, we utilized recombinant DNA technology and protein engineering methods to engineer and reconfigure the enzyme in new ways.”
Those engineering methods included circular permutation (CP) by protein design, to enhance stability and make the enzyme easier to produce, and pegylation, which improves the enzyme’s pharmacokinetics—the properties that allow it to be absorbed and properly distributed within the body. The new enzyme is known as PEG-CapD-CP(S334C).
In the study, 80% to 100% of mice treated with the enzyme survived anthrax infection, compared with 10% to 20% of mice that received a control treatment.
"These findings suggest that enzyme-catalyzed removal of the capsule may be a potential therapeutic strategy for the treatment of multi-drug resistant anthrax and other bacterial infections," the authors wrote.
It could also allow warfighters exposed to anthrax to be treated at the time of exposure or shortly thereafter, preserving combat power in scenarios where advanced diagnostics and treatments may not be readily available.
Read the study: https://www.science.org/doi/10.1126/scitranslmed.abh1682