New Aspects of Protein Biosynthesis Inhibition by Proline-Rich Antimicrobial Peptides.

Proline-rich antimicrobial peptides (PrAMPs) are promising compounds for overcoming antibiotic resistance, one of the global health threats, and stand out from other types of AMPs by their high safety profile. The main cellular target of PrAMPs, like most modern antibiotics, is the conservative cellular structure - the ribosome. PrAMPs bind in the ribosomal tunnel, forming multiple interactions with nucleotides of 23S rRNA, and are divided into two classes depending on their mechanism of action: inhibition of elongation or termination. The N-terminal part of the peptides, which is important for the activity of class I peptides, extends into the A-site pocket, preventing the binding of aminoacyl-tRNA. A new family of PrAMPs, rumicidins, was discovered using genomic search methods. Its representatives have the longest N-terminal part, as well as a unique pair of amino acids Trp23 and Phe24 at the C-terminus. The Trp-Phe dyad forms a spacer at the constriction site of the ribosomal tunnel, stabilizing the binding and leading to increased antibacterial activity. New structural studies of the class I peptide Bac5 have demonstrated its ability to disrupt the correct positioning of the CCA-end of the P-site tRNA in the peptidyltransferase center of the ribosome, which can affect the assembly of functional initiation complexes. Class II PrAMPs, according to new data, have additional binding sites on the ribosome and have a complex effect on the bacterial cell: they disrupt the termination of protein synthesis, block the cellular ribosome release system, prevent the correct assembly of the 50S ribosomal subunits, and, possibly, affect the first stage of translocation. Recent studies expand our understanding of the antimicrobial activity of PrAMPs and contribute to the creation of future therapeutic drugs based on AMPs.