A University of Pittsburgh researcher has developed novel cationic antimicrobial peptides (AMPs) through modification of secondary structure and the associated amphipathic characteristics. AMPs are cationic peptides, typically 12–50 peptides in length, and demonstrate antimicrobial properties against treatment-resistant pathogens. This novel approach of changing the amphipathic character of AMPs could unleash the full therapeutic potential of this class of medication and play a pivotal role in tackling antimicrobial resistance (AMR), one of the world’s leading public health challenges.
Novel AMPs have been developed. Based on peptides in existing AMPs the secondary structure has been scrambled to change the amphipathic from helical to linear. The secondary structure of these novel AMPs is fixed with chemical bonds (e.g., disulfide bridges). This rearrangement could lead to the development of more effective antimicrobial therapies against treatment resistant microbes.
Description
AMR, where bacteria, viruses, fungi, or parasites no longer respond to medication is linked to nearly 5 million deaths globally each year. It remains a major threat to global public health and threatens to undo many medical advances of recent times. Without effective antimicrobial therapies, procedures like cesarean sections, chemotherapy and routine surgeries will become risker. There is a critical need for new antimicrobial therapeutics to counter AMR, for animal as well as human health, to ensure food supply. AMPs have shown some promise against treatment-resistant microbes, but their clinical application has been limited by toxicity issues. Using a novel design strategy, new AMPs have been synthesized with initial studies suggesting similar or better antimicrobial activity with lower levels of toxicity compared to existing AMPs. These novel AMPs could provide solutions to the global AMR crisis, potentially saving millions of lives.
Applications
- Treatment-resistant infections
Advantages
Current AMPs have been engineered to produce idealized helical amphipathicity (H-amph) where cationic (C) and hydrophobic (H) amino acids are on opposite sides of a helical structure. The H-amph approach was believed to be crucial to the ability of AMPs to target lipids on bacterial surfaces. However, AMPs exhibit some toxicity, limiting their clinical use.
This novel AMP design has linear amphipathicity (L-amph) with C and H amino acids grouped into separate motifs side by side in the linear structure (compared to H-amph where C and H amino acids are scrambled in the linear structure). L-amph AMPs can form helical structures with low μH (a measure of H-amph). Initial results suggest these L-amph AMPs exhibit antimicrobial activity with less toxicity. Additionally, L-amph AMPs can be head-to-tail cyclized and fused using disulfide bridges enhancing their therapeutic properties, unlike H-amph where cyclization inhibits activity. This ability to produce AMPs of varying secondary structures may lead to the development of a new class of AMPs to safely tackle AMR.
Invention Readiness
In vivo studies demonstrated L-amph AMP antimicrobial activity against linezolid resistant Staphylococcus. In vitro membrane perturbation studies suggesting L-amph AMPs may have a different mechanism of action. Cyclization of L-amph AMPs further enhanced the antimicrobial activity with reduced lytic effects on red blood cells. Further studies are required.
IP Status
https://patents.google.com/patent/US20240197823A1
