Designing an enzyme to treat anthrax without antibiotics


Researchers have taken a step towards developing a treatment that can treat infection of antibiotic-resistant strains of anthrax in mice without antibiotics.

Anthrax-causing spores were mailed to news agencies and members of Congress during the 2001 “Amerithrax” attacks, sickening at least 22 people and killing five. Researchers are preparing to fight antibiotic-resistant variants of the bacteria, which are a growing cause for concern. Now a team has made progress towards creating a therapy that can treat the infection in mice without the use of antibiotics, as reported today (September 14, 2022) in the journal SCA Infectious Diseases.

Bacillus anthracis is a type of gram-positive rod-shaped bacteria that can cause anthrax infection by exposure to its spores, either by ingestion, inhalation or a cut in the skin. Anthrax infection can lead to breathing difficulties, skin ulcers or even death. Although there are antibiotics for anthrax, resistance to these drugs can develop over time.

Enzyme designed against antibiotic resistant anthrax

This enzyme designed with bits of antibody stuck on it can break the capsule of the B. anthracis bacteria, allowing the immune system to fight back. Credit: Adapted from ACS Infectious Diseases, DOI: 10.1021/acsinfecdis.2c00227

A kind of B.anthraciscalled the Ames strain, is particularly virulent because the bacterium can wrap itself in a protective capsule of poly-D-glutamic acid. This acts as an invisibility cloak, which helps bacteria evade the human immune system. A B.anthracis an enzyme called CapD anchors the capsule material to the bacteria. However, previous studies have reported that the enzyme may be engineered to degrade the capsule instead, making the bacteria susceptible to the immune system.

Studies have also shown that providing mice with modified CapD can help treat an Ames strain anthrax infection without the use of antibiotics. Additionally, Patricia Legler and her colleagues demonstrated that adding polyethylene glycol (PEG) to this version of CapD can help the enzyme last longer, thereby increasing mouse survival. In this new study, the research team wanted to optimize the treatment even further.

To make the revamped enzyme last longer in the body and deliver a bigger punch, the scientists added PEG and fused the CapD protein with part of a mouse antibody. This resulted in the binding of two CapD enzymes, which would essentially double its binding power to the capsule. The research team created several versions of the enzyme and put them through many rounds of optimization, removing and inserting different segments until they got a sequence that retained its 3D shape and behaved as expected over a range of pH values.

When tested in a mouse model, this construct lasted longer than the previous version without the fused antibody, although it had reduced activity. Scientists say more research is needed to produce the ideal construct, but the results are an important step towards better treatment for antibiotic-resistant bacteria. B.anthracis strains.

Reference: “Engineering an Fc-fusion of a Capsule Degrading Enzyme for Treatment of Anthrax” September 14, 2022, SCA Infectious Diseases.
DOI: 10.1021/acsinfecdis.2c00227

The authors acknowledge funding from the Defense Threat Reduction Agency.


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