Antibiotic resistance is a significant public health problem, with bacterial infections becoming increasingly difficult to treat. In 2019, around 35,000 people in the U.S. alone died from antibiotic-resistant infections. Most antibiotics used today have been available for decades. The development of new ones has proceeded slowly.
Researchers have recently been using computational methods to design very small pieces of protein, called peptides, as alternatives to conventional antibiotics. Rather than design new peptides, a research team led by Dr. Cesar de la Fuente-Nunez from the University of Pennsylvania turned to the human body as a potential source of new antibiotics.
Almost all living organisms produce peptides that help defend the body from infection. Many have other functions, such as helping with digestion and blood circulation. But they also appear to play a role in the body’s defense against pathogens.
To identify peptide antibiotics, the team used artificial intelligence to screen the entire human proteome—the set of all proteins in the human body. They searched for peptides hidden in the proteome, called encrypted peptides, with specific traits that hint at antibacterial properties.
The study was funded in part by NIH’s National Institute of General Medical Sciences (NIGMS). Results were published on November 4, 2021, in Nature Biomedical Engineering.
An initial scan of the proteome identified about 2,600 encrypted peptides with potential antibiotic properties. The team selected 55 top candidates and synthesized them in the lab for further testing. In cultures of eight common infectious bacteria, more than 60% of the peptides showed some ability to kill at least one of the microbes.
Unexpectedly, these peptides also had low-level effects on bacteria commonly found in the gut and on the skin. This suggests that they may play a role in maintaining a healthy balance between the human body and its resident microbes.
The team found that combinations of peptides from the same area of the body were more potent than single peptides against infectious bacteria. For example, a combination of three peptides increased their ability to kill a bacterium called A. baumannii by 100-fold.
In mouse studies, a combination of two of the most potent peptides decreased the number of bacteria found in skin infections by five to six orders of magnitude. This reduction was comparable to that seen with some standard antibiotics.
When the team delivered a combination of peptides to wounds deeper within the leg, they saw a reduction in bacteria of up to three orders of magnitude. The mice did not lose weight during any of the experiments, suggesting that such treatments would be safe.
Further studies showed that the peptides appeared to work by damaging the outer membrane of targeted bacteria. Microbes are less likely to be able to develop resistance to this type of attack than to the types of damage caused by current antibiotics.
“A surprising finding was that these peptides were not only encoded in the immune system but were also found in the digestive, circulatory, and nervous systems, for example, indicating that fighting off infections caused by invading organisms may be a more holistic approach than previously thought,” de la Fuente says.
Encrypted peptides are already optimized by nature and produced in our own bodies. With further work, they may be promising candidates for antibiotic development.
