Ingeniería de una enzima para tratar el ántrax sin antibióticos

Las esporas que causan el ántrax se enviaron por correo a organizaciones de noticias y miembros del Congreso durante los ataques “Amerithrax” de 2001, que enfermaron al menos a 22 personas y mataron a cinco. Los investigadores se están preparando para combatir las variantes resistentes a los antibióticos de la bacteria, que son una fuente creciente de preocupación. Ahora, un equipo ha avanzado hacia la creación de una terapia que puede tratar la infección en ratones sin el uso de antibióticos, como se informó hoy (14 de septiembre de 2022) en la revista ACS Enfermedades Infecciosas.

Bacillus Anthracis es un tipo de bacteria grampositiva con forma de bastoncillo que puede causar[{” attribute=””>anthrax infection through exposure to its spores, either by ingestion, inhalation, or a cut in the skin. Anthrax infection can lead to difficulty breathing, skin ulcers, or even death. Although antibiotics against anthrax exist, resistance to these drugs can occur over time.

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

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

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

To improve the re-engineered enzyme’s lifetime 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 two CapD enzymes bound together, which would essentially double its capsule-binding power. The research team created several versions of the enzyme and subjected them to many rounds of optimization, deleting and inserting different segments until they achieved a sequence that both held its 3D shape and performed as expected in a range of pH values.

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

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

The authors acknowledge funding from the Defense Threat Reduction Agency.