Antibiotic resistance is a growing global health crisis, rendering many common bacterial infections increasingly difficult to treat. Now, researchers are exploring novel approaches to combatting these resilient pathogens, including chemically modifying naturally occurring antimicrobial peptides. A recent study, published in and further detailed in findings released on , suggests that altering the structure of these peptides can significantly enhance their effectiveness against tuberculosis (TB) while reducing potential toxicity.
The World Health Organization issued a warning last highlighting the increasing ineffectiveness of antibiotics against a range of bacterial pathogens, including E. Coli, K. Pneumoniae, Salmonella, and Acinetobacter. For Mycobacterium tuberculosis, the bacterium responsible for TB, a team from Penn State and the University of Minnesota Medical School investigated whether chemically modifying host-defense peptides (HDPs) could offer a solution. HDPs are short chains of amino acids naturally produced by the body and have shown promise as potential treatments for antibiotic-resistant infections.
“There’s a desire to create new drugs that can kill bacteria through mechanisms that are not used by traditional antibiotics,” explained Scott Medina, Korb Early Career Associate Professor of Biomedical Engineering at Penn State and the study’s corresponding author. “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 target specific biochemical pathways within bacteria, pathways to which bacteria can develop resistance through mutations. HDPs offer a different approach, but they often suffer from instability, being rapidly broken down by enzymes in the body. To overcome this limitation, the researchers employed a combination of chemical techniques – “backbone-inversion” and chirality switching – to create more resilient peptides.
Backbone-inversion reverses the direction of the peptide’s structural framework, while chirality switching alters the molecule’s spatial orientation. The goal was to protect the peptides from enzymatic degradation, increasing their stability and extending their antibacterial effects. However, the team discovered an unexpected benefit.
The retro-inverted variant, created through these modifications, wasn’t just more stable; it was also dramatically more potent against the tuberculosis pathogen and less toxic to human cells compared to the original, unmodified molecule. “When we compared the original molecule 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.”
Further investigation, utilizing microscopy and structural analysis, revealed the mechanism behind this enhanced activity. The altered shape imparted by the retro-inversion made it energetically more favorable for the HDPs to penetrate the protective cell membranes of the bacteria. This physical disruption of the membrane, rather than targeting specific bacterial proteins, represents a fundamentally different mode of action than traditional antibiotics.
Research published in in Pharmaceuticals highlights the broader potential of peptide-based strategies against Mycobacterium tuberculosis, encompassing immunomodulation, vaccine development, synergistic therapies, and nanodelivery systems. This underscores the growing interest in harnessing the power of peptides to combat TB.
The researchers believe this new mechanism makes it more difficult for bacteria to develop resistance. Instead of evolving mutations to bypass a specific drug target, bacteria would need to fundamentally alter their cell membrane structure, a more challenging feat. A review published in Archives of Microbiology notes that antimicrobial peptides (AMPs) exhibit dual benefits: bactericidal activity against Mtb and immunoregulatory properties, making them strong contenders for alternative or adjuvant therapies.
However, the researchers emphasize that this modified peptide is not intended as a replacement for existing TB treatments. “We don’t envision that this is a drug that’s going to entirely replace current TB therapies,” Medina stated. “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.” This synergistic approach could be crucial in combating the rise of multi-drug-resistant (MDR) mycobacterial strains, a significant challenge highlighted by researchers in the Pharmaceuticals publication.
Further research is needed to fully evaluate the potential of these modified peptides in clinical settings. However, this study represents a promising step forward in the development of new strategies to combat antibiotic resistance and improve the treatment of tuberculosis, a disease that continues to pose a significant threat to global public health. A separate study, detailed in a January publication, focused on structuring peptides, specifically LLAP, to increase potency against M. Smegmatis, further demonstrating the potential of peptide modification.
