Modified peptides show promise against tuberculosis bacteria

Antibiotic treatments are losing effectiveness against a range of common bacterial pathogens, including E. coli, K. pneumoniae, Salmonella and Acinetobacter, according to a warning issued by the World Health Organization last October. For the microbe that gives rise to tuberculosis, a team of researchers from Penn State and The University of Minnesota Medical School found that a potential solution may be chemically changing the structure of a naturally occurring peptide - a building block of proteins - to make it a more stable and effective antimicrobial agent, while reducing potential toxicity to human cells.

The synthetically structured peptides could potentially help the cocktail of drugs used to treat tuberculosis be more effective, according to the researchers. They published their work in Nature Communications.

"There's a desire to create new drugs that can kill bacteria through mechanisms that are not used by traditional antibiotics," said Scott Medina, Korb Early Career Associate Professor of Biomedical Engineering at Penn State and corresponding author on the paper. "Particularly, there is an interest in molecules that may be difficult for bacteria to evolve resistance towards, providing a longer span of time for these treatments to be clinically useful."

Traditional antibiotics often work by inhibiting biochemical pathways that are susceptible to resistance mutations - which bacteria evolve to evade the antibiotics. To find an alternative, the researchers started with host-defense peptides (HDPs), short chains of amino acids that are produced naturally in the body and have been identified as potential treatments for antibiotic-resistant infections. However, these therapies are often unstable and quickly degraded by natural enzymes in the body.

Seeking a more stable compound, the team applied combinations of chemical techniques to make the peptides more resilient to enzymes: "backbone-inversion," which reverses the direction of the structural framework; and chirality, or "handedness," switching, which alters the spatial orientation of the molecule.

"We knew that the peptide could kill bacteria cells, and specifically the mycobacteria that cause tuberculosis," Medina said. "We initially set out to use these chemical tweaks to make the treatment more stable in the body, so it would be around longer and therefore extend its antibacterial effects."

The team found that the retro-inverted variant was not only more stable, but was dramatically more potent against the tuberculosis pathogen and less toxic to human cells compared to the original molecule.

"When we compared the original molecule - which doesn't have any chemical modifications - to the one that we did modify, not only was the modified one more stable, but now it was also much more active," Medina said. "That's something that we didn't expect to see."

Using various microscopy and structural analysis techniques, the researchers identified the cause of the phenomenon: the new shape imparted by the retro-inversion made it more energetically efficient for HDPs to penetrate protective bacterial cell membranes.

Medina said that inverted HDPs work via a different mechanism than traditional antibiotics. Instead of disrupting protein targets important to bacterial survival, the inverted HDPs physically degrading the membrane to destroy the pathogen and make it more difficult for the bacteria to evolve the mutations needed to become resistant.

"There's definitely more that needs to be done," Medina said. "We don't envision that this is a drug that's going to entirely replace current TB therapies. Rather, we think the biggest value of our molecule is its potential to enhance the activity of current TB drugs when given together, making the current treatments much more effective."