Antimicrobial and Amyloidogenic Activity of Peptides Synthesized on the Basis of the Ribosomal S1 Protein from Thermus Thermophilus

Abstract

Controlling the aggregation of vital bacterial proteins could be one of the new research directions and form the basis for the search and development of antibacterial drugs with targeted action. Such approach may be considered as an alternative one to antibiotics. Amyloidogenic regions can, like antibacterial peptides, interact with the “parent” protein, for example, ribosomal S1 protein (specific only for bacteria), and interfere with its functioning. The aim of the work was to search for peptides based on the ribosomal S1 protein from T. thermophilus, exhibiting both aggregation and antibacterial properties. The biological system of the response of Gram-negative bacteria T. thermophilus to the action of peptides was characterized. Among the seven studied peptides, designed based on the S1 protein sequence, the R23I (modified by the addition of HIV transcription factor fragment for bacterial cell penetration), R23T (modified), and V10I (unmodified) peptides have biological activity that inhibits the growth of T. thermophilus cells, that is, they have antimicrobial activity. But, only the R23I peptide had the most pronounced activity comparable with the commercial antibiotics. We have compared the proteome of peptide-treated and intact T. thermophilus cells. These important data indicate a decrease in the level of energy metabolism and anabolic processes, including the processes of biosynthesis of proteins and nucleic acids. Under the action of 20 and 50 μg/mL R23I, a decrease in the number of proteins in T. thermophilus cells was observed and S1 ribosomal protein was absent. The obtained results are important for understanding the mechanism of amyloidogenic peptides with antimicrobial activity and can be used to develop new and improved analogues.

Antimicrobial and Amyloidogenic Activity of Peptides. Can Antimicrobial Peptides Be Used against SARS-CoV-2?

“…At the same time, using computational and experimental approaches, we described specific amyloidogenic regions within the domains of the S1 protein, which can be potential sites for modulating the aggregation properties of bacterial ribosomal S1 proteins [ 9 , 205 , 206 , 207 ]. Based on the predicted amyloidogenic regions, amyloidogenic peptides were synthesized, some of which exhibited antimicrobial activity in vitro tests [ 16 ].…”

“…Self-aggregation of a protein or its coaggregation with an effector peptide should lead to blocking of protein functions and a decrease in the viability of the bacterial cell. In our study, we used methods of thioflavin T fluorescence, electron microscopy, spectrophotometry and mass-spectrometry to assess the amyloidogenic and antibacterial activity of peptides synthesized on the basis of the ribosomal S1 protein from Thermus thermophilus [ 16 ]. It has been experimentally demonstrated that amyloidogenic regions of the ribosomal S1 protein can be used as candidates for the development of new antibacterial peptides [ 16 ].…”

“…The same work discusses the possible role of the amyloidogenic sequence in the performance of protein E of its functions of binding to the host cell membranes and formation of ion channels. In our opinion, the amyloidogenic region in the middle of SARS-CoV-2 protein S can be the basis for the development of AMPs acting by the mechanism of directed coaggregation [ 16 ]. We hypothesize that anti-CoV peptides can bind to RBD of spike S1 protein ( Figure 6 ).…”

“…In turn, we proposed another mechanism of the antimicrobial action of peptides, based on the directed coaggregation of the amyloidogenic peptide with the target protein and the subsequent dysfunction of this protein. Using programs predicting amyloidogenic regions in a protein molecule, sequences of peptides with a tendency to aggregate with the target protein were selected [ 16 ]. It is important that the potential for use of peptides combining antimicrobial and amyloidogenic properties is not limited to their use against antibiotic-resistant bacteria.…”

Identification of Amyloidogenic Regions in Pseudomonas aeruginosa Ribosomal S1 Protein

“…It is important that the S1 domain is a structural variant of the oligosaccharide/oligonucleotide-binding fold (OB-fold) [ 23 , 24 ] and can exhibit amyloidogenic properties, like another analog of the OB-fold, the cold shock domain [ 25 ]. Previously, peptides with amyloidogenic properties and antimicrobial activity against Thermus thermophilus were synthesized and studied based on the sequences of the S1 domains of the ribosomal S1 protein of the model organism T. thermophilus [ 26 ].…”