Dartmouth Engineer - The Magazine of Thayer School of EngineeringDartmouth Engineer - The Magazine of Thayer School of Engineering

Protein Engineering Helps Fight MRSA Infections

By Anna Fiorentino
June 2015 • CoolStuff

Dartmouth engineering professor Karl Griswold and his research team have found a way to combat the spread of methicillin-resistant Staphylococcus aureus (MRSA). This bacterium—often contracted during surgeries and other invasive healthcare procedures— kills more patients than any other drug-resistant pathogen, according to the CDC.

Together, Griswold and Dartmouth computer science professor Chris Bailey-Kellogg have used protein engineering to redesign lysostaphin—an enzyme that can fight MRSA but has been limited by the human immune response.  

Karl Griswold and Hongliang Zhao
Prof Karl Griswold & research assoc Hongliang Zhao

"The human body perceives lysostaphin as a foreign invader and mounts an immune response against it. In other words, the body attacks lysostaphin," says Griswold. 

To produce a better drug candidate, the researchers made lysostaphin invisible to the human immune system by identifying and "deleting" immunogenic epitopes embedded in the natural lysostaphin protein.

"These T cell epitopes are short peptide fragments within foreign proteins that represent red flags to the human immune system," says Griswold, whose team includes BE, MS, and PhD engineering students and research associates. To delete the epitopes, the team introduced amino acid substitutions, or mutations, into lysostaphin and created new versions of the natural molecule.

Chris Bailey-Kellogg and Deeptak Verma
Prof Chris Bailey-Kellogg & postdoc Deeptak Verma

Two of their studies on deimmunized lysostaphin have recently been published. One appearing in Molecular Therapy—Methods and Clinical Development, describes how deimmunized lysostaphin hides from the body's immune cells. The second in Chemistry and Biology shows how deimmunized lysostaphin is better able to treat MRSA infections in mice that have partially humanized immune systems (http://authors.elsevier.com/a/1R3kl3qKof6taB).

"We now have a highly engineered version of lysostaphin that produced impressive results in some preliminary experiments," says Griswold. "The tests are progressing, but there’s still a lot of work to be done."

The lysostaphin project is part of a larger collaboration between the two Dartmouth engineering and computer science research groups. Their work over the past eight years has led to a biotech startup called Stealth Biologics LLC that's working with biopharma partners to develop deimmunized drug candidates. In conjunction with Dartmouth, Stealth Biologics has also secured a National Institutes of Health grant to continue developing the deimmunized lysostaphin molecule. They filed for a joint patent in May.

"Stealth was not formed around the lysostaphin project, but rather the lysostaphin project is just one thing the company is working on," says Griswold. "We have several biopharma partners and clients with whom we are pursuing deimmunization projects on other unrelated molecules."

Tags: engineering in medicine, entrepreneurship, faculty, patent, research

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