According to the WHO prognosis, infections caused by microorganisms resistant to conventional antibiotics will be the leading cause of death worldwide by 2050.  To combat antibacterial resistance, novel compounds exerting unique actions are needed. Researchers at HUN-REN RCNS have reported their first promising results of a potent alternative in this direction, published in the prestigeous journal Nature Communications in April 2024.

The researchers designed supramolecular assemblies, which combine the complex bacteria attacking mechanisms of natural host defense peptides with the improved biostability of non-natural compounds. To target Gram-negative bacteria, they employed a design strategy utilizing lysine-rich cationic peptides built up of non-natural amino acids.

The strategy focused on an inducible assembly mechanism where the key parameter is the inter-lysine distance in the peptides matching the inter-phosphate distance of lipopolysaccharide species abundant on the bacterial cell surface. This way, supramolecular assembly formation is triggered by the bacterium in-situ, and the process can be depicted using electron microscopy.

Indeed, micrographs proved the working concept for the designed peptides and unveiled details of their mechanism of action. It has been shown that the forming lamellae incised the cell envelope and protruded into the target cell, thereby causing leakage and subsequently killing bacteria. Surprisingly, detailed image analysis indicated that a few of the penetrating supramolecules are sufficient to cause major cell wall damage. In line with this data, antibacterial activity assays proved that inhibition of bacterial growth starts already at submicromolar peptide concentrations.

Combined molecular dynamics simulations and elctron microscopy imaging confirmed that supramolecular assembly formation is induced by anionic phosphate groups. Indeed, the striped lamellar morphology is formed even in the presence of simple inorganic phosphate ions, where each stripe represents double arrays of hydrogen-bonded peptide molecules that are interconnected by the phosphates.  

The reported innovative findings provide mechanistic details on a peptide-based supramolecular antibiotic, the activity of which is triggered in-situ by the bacteria, whilst a direct visual insight gained here has not been captured for the action of a bactericidal peptide yet.

Structure and mechanism of the designed peptide lamellae.