Lab Report: Treatment for Drug-Resistant Bacterial Infections

Image courtesy of Karl Griswold.

The Centers for Disease Control and Prevention (CDC) has prioritized finding effective treatment of methicillin-resistant Staphylococcus aureus (MRSA), one of the most common bacterial pathogens and the single most deadly drug-resistant bacteria in the United States. A new study led by Dartmouth engineers shows promise for a lysin-based antibacterial agent that may enable safe, repeated dosing to treat life-threatening staph infections.

In recent years, lysins—enzymes naturally produced by microbes and associated viruses—have shown potential to treat S. aureus, which can rapidly acquire resistance to other types of antibiotic drugs.

“Lysins are one of the most promising next-generation antibiotics,” says Professor Karl Griswold. “They kill drug-sensitive and drug-resistant bacteria with equal efficacy, they can potentially suppress new resistance phenotypes, and they also have this laser-like precision.”

While there is promise in lysins, development has been slowed due to concerns they prompt humans’ immune systems to develop antidrug antibodies, which can have negative side effects, including life-threatening hypersensitivity reactions.

F12 is a new lysin-based antibacterial agent engineered and patented by a team that includes researchers in Dartmouth’s computer science department, the Lundquist Institute at Harbor-UCLA Medical Center, Lyticon, and Stealth Biologics.

The agent is essentially able to hide from the human immune system, and so does not cause the same negative side effects as natural lysins. It is also the first lysin-based treatment with the potential to be used multiple times on a single patient.

“We have engineered this super-potent, super-effective anti-MRSA biotherapeutic, and we’ve done it in a way that renders it compatible with and largely invisible to the human immune system. By making it a safer drug, we’ve enabled the possibility of dosing multiple times in order to treat even the most highly refractory infections,” says Griswold.

The team’s paper, “Globally deimmunized lysostaphin evades human immune surveillance and enables highly efficacious repeat dosing,” was published in Science Advances last fall. The work was the result of two grants totaling $1.7 million from the National Institutes of Health.

The paper details the treatment’s positive results in rabbits, mice with partially humanized immune systems, and studies with extracted human immune cells. “This is the first report of a translation-ready deimmunized lysin, and F12 has serious, bona fide clinical potential,” says Griswold.

The antibacterial agent could be ready for human clinical trials as soon as 2023.