A University of Alberta research team has designed a promising alternative for treating antimicrobial-resistant infections, a pressing global health issue.
In a recently-published paper, the team describes preclinical testing results for its human-derived peptide treatment, D-GK17.
The peptide is stable and non-toxic to humans and is synthesized to attack the surfaces of bacteria or fungi cells that create biofilms, a sticky matrix that is often impenetrable to antibiotic treatments.
“Antimicrobial resistance is the biggest pandemic threatening humanity, so we really need potent antibiotic alternatives to which bacteria are unable to develop resistance,” says principal investigator Dr. Prasanna Neelakantan, associate professor in the Mike Petryk School of Dentistry and Alberta Dental Association & College Chair in Oral Health Research, who did the work with collaborators at the University of Hong Kong and the University of Pennsylvania.
“Our peptide shredded bacterial biofilms, which cause up to 75 per cent of life-threatening infections,” Neelakantan explains. “We used skin infection models to show how our antibiotic alternative not only rescues from devastating bacterial infections, but also reduces inflammation and promotes wound healing.”
Antimicrobial resistance is estimated to have directly caused 1.27 million deaths and contributed to 4.95 million deaths in 2019, according to the World Health Organization.
The team’s treatment is based on a human-produced host defense peptide that provides rapid broad-spectrum protection against bacteria, viruses and fungi. Most such peptides are toxic in the high concentrations that are needed to eradicate biofilms, and more importantly, they are unstable in body fluids, so it has been hard to harness their power as drugs.
The Neelakantan team serendipitously discovered a small subunit of the human peptide LL-37 known as GK17, that is stable and non-toxic, first publishing their findings three years ago.
“It checked the box for killing bacteria and fungi. It checked the box for preventing the development of resistance. But one box that it did not check was whether it could eradicate biofilms, which would be critical. So, we made a mirror-version of our peptide, hoping it would break down biofilms,” says Neelakantan.
They tested it against the biofilms created by the so-called ESKAPE group of the world’s most critical pathogens, and it worked.
“Almost no antibiotic works against the biofilms of these organisms, so we asked if our inverse GK17, that is Dextro-GK17, could kill these bacteria and also eradicate biofilms, and very excitingly, it was able to do that, both as a topical application and by injection into the body,” he says.
Neelakantan explains that the peptide works by attacking the membranes of pathogen cells, creating pores that cause the cells to fail. He’s especially pleased to see that the peptide works against fungi.
“While several labs in the world focus on bacteria and viruses, our group has a special focus on fungi because fungi are the key driver of disease and death for immune compromised people. This includes patients with cancer, AIDS or on steroid therapy, as well as very young and very old patients,” Neelakantan says.
“Alarmingly, we only have four types of antifungal drugs and fungi are resistant to all four categories already.”
The team is filing a patent through the U of A for use of the peptide against both bacteria and fungi and are working to develop delivery mechanisms, including a gel to treat skin infections and a bandage to be applied inside the mouth to treat ulcers caused by cancer. In collaboration with Dr. Ted Allison, professor in the Faculty of Science, Neelakantan has received funding from the Women and Children’s Health Research Institute to test the peptide as a treatment for sepsis in newborns.
Neelakantan says the team is eager to begin human clinical trials.
“As academics we do research for the love of research, but the end goal is that it has to reach a patient.”
This research was supported by Prasanna Neelakantan’s endowed Alberta Dental Association & College Chair in Oral Health Research, funding from the Mike Petryk School of Dentistry and a Mitacs Globalink Research Award. Neelakantan is a member of the Women and Children’s Health Research Institute, the Li Ka Shing Institute of Virology and the Cancer Research Institute of Northern Alberta. He holds an adjunct position with the Department of Medical Microbiology and Immunology.