A research team from Penn State and The University of Minnesota Medical School has developed a new approach to fight tuberculosis by chemically modifying naturally occurring peptides. Their findings, published in Nature Communications, suggest that these modified peptides could help make current tuberculosis drug regimens more effective.
The study comes amid concerns about the decreasing effectiveness of antibiotics against common bacteria such as E. coli, K. pneumoniae, Salmonella, and Acinetobacter. The World Health Organization issued a warning last October about this growing threat.
Scott Medina, Korb Early Career Associate Professor of Biomedical Engineering at Penn State and corresponding author on the paper, explained the motivation behind the research: "There's a desire to create new drugs that can kill bacteria through mechanisms that are not used by traditional antibiotics. 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 typically target biochemical pathways in bacteria. However, bacteria often develop resistance through mutations. To address this challenge, the researchers focused on host-defense peptides (HDPs), which are naturally produced in the body and have potential as treatments for antibiotic-resistant infections. These peptides tend to be unstable and degrade quickly inside the body.
To improve their stability and potency, the scientists used chemical techniques such as "backbone-inversion," which reverses the structural direction of the peptide framework, and chirality switching to alter its spatial orientation.
"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 results showed that a retro-inverted version of the peptide was not only more stable but also significantly more effective against tuberculosis bacteria while being less toxic to human cells than its unmodified counterpart.
"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."
Microscopy and structural analysis revealed that retro-inversion changed how HDPs interact with bacterial membranes. This made it easier for them to penetrate cell membranes and destroy pathogens without relying on traditional antibiotic targets.
Medina noted: "There's definitely more that needs to be done. 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."
