Is It Possible to Create Antimicrobial Peptides Based on the Amyloidogenic Sequence of Ribosomal S1 Protein of P. aeruginosa?

Abstract

The development and testing of new antimicrobial peptides (AMPs) represent an important milestone toward the development of new antimicrobial drugs that can inhibit the growth of pathogens and multidrug-resistant microorganisms such as Pseudomonas aeruginosa, Gram-negative bacteria. Most AMPs achieve these goals through mechanisms that disrupt the normal permeability of the cell membrane, which ultimately leads to the death of the pathogenic cell. Here, we developed a unique combination of a membrane penetrating peptide and peptides prone to amyloidogenesis to create hybrid peptide: “cell penetrating peptide + linker + amyloidogenic peptide”. We evaluated the antimicrobial effects of two peptides that were developed from sequences with different propensities for amyloid formation. Among the two hybrid peptides, one was found with antibacterial activity comparable to antibiotic gentamicin sulfate. Our peptides showed no toxicity to eukaryotic cells. In addition, we evaluated the effect on the antimicrobial properties of amino acid substitutions in the non-amyloidogenic region of peptides. We compared the results with data on the predicted secondary structure, hydrophobicity, and antimicrobial properties of the original and modified peptides. In conclusion, our study demonstrates the promise of hybrid peptides based on amyloidogenic regions of the ribosomal S1 protein for the development of new antimicrobial drugs against P. aeruginosa.

Multiple Antimicrobial Effects of Hybrid Peptides Synthesized Based on the Sequence of Ribosomal S1 Protein from Staphylococcus aureus

“…We were guided by the idea that a peptide with an amyloidogenic region will interact with a target protein containing the same amyloidogenic site. We sequentially tested the developed antimicrobial peptides containing amyloidogenic regions of the ribosomal S1 protein, first against model organisms ( T. thermophilus and E. coli ) [ 27 ], then against pathogenic microorganisms ( P. aeruginosa and S. aureus ) [ 29 ].…”

“…The N-terminus of synthesized hybrid peptides contains a cell-penetrating peptide (CPP) fragment RKKRRQRRR connected to the amyloidogenic region using a linker of three glycine and sarcosine residues (GG-Sar-G) [ 29 ]. In addition, the R23F peptide was synthesized with an amino acid modification (Asi19 instead of Asn19).…”

“…Antimicrobial peptides, in addition to antibacterial activity, can exhibit various biological effects, for example, antidiabetic action [ 59 ], anti-cancer effects of some AMPs have been shown [ 60 , 61 ]. It is known that minor changes in the primary structure of AMP can significantly affect not only the antimicrobial efficiency of peptides but also their mechanism of action [ 29 , 62 ].…”

“…They allow to deliver “cargo” into the cell and do not have significant membranolytic effects [ 28 ]; in addition, they perform specific functions of peptides associated with self-assembly [ 27 ]. Based on the recent results of studying hybrid peptides based on combinations of TAT-peptide fragments and amyloidogenic regions of bacterial ribosomal S1 proteins, we suggest that amyloidogenic propensity may significantly contribute to the antimicrobial effect of synthetic antimicrobial peptides [ 29 ].…”

“…It is known that amyloidogenic proteins and peptides of bacteria can participate in biofilm formation and thus enhance bacterial infection [ 39 ]. On the other hand, coaggregation of hybrid peptides with amyloidogenic regions of ribosomal proteins of bacteria can lead to disruption of their functioning, which means that such hybrid peptides can exhibit antimicrobial effects [ 29 , 40 ]. The targeted action of the R23I peptide was shown in experiments on T. thermophilus .…”