Abstract
Antimicrobial peptides (AMPs) and similar compounds are potential candidates for combating antibiotic-resistant bacteria. The hypothesis of directed co-aggregation of the target protein and an amyloidogenic peptide acting as an antimicrobial peptide was successfully tested for peptides synthesized on the basis of ribosomal S1 protein in the bacterial culture of T. thermophilus. Co-aggregation of the target protein and amyloidogenic peptide was also tested for the pathogenic ribosomal S1 protein from P. aeruginosa. Almost all peptides that we selected as AMPs, prone to aggregation and formation of fibrils, based on the amino acid sequence of ribosomal S1 protein from E. coli, T. thermophilus, P. aeruginosa, formed amyloid fibrils. We have demonstrated that amyloidogenic peptides are not only toxic to their target cells, but also some of them have antimicrobial activity. Controlling the aggregation of vital bacterial proteins can become one of the new directions of research and form the basis for the search and development of targeted antibacterial drugs.
Highlights
Antibiotic resistance of bacteria is a pressing global problem
We have proposed a new mechanism of antimicrobial peptides (AMPs) action, a mechanism of directed co-aggregation, which is based on the interaction of a peptide capable of forming fibrils with a target protein
The selection of fragments of the amino acid sequence of peptides with potential antimicrobial properties should include other characteristics in addition to the presence of amyloidogenic regions, for example, cell penetrating peptides, which, as we have shown with Tat-HIV-1 (49–57) peptide, for example, weaken the aggregation properties, but enhance the antimicrobial effect of the peptide (Kurpe et al, 2020)
Summary
Antibiotic resistance of bacteria is a pressing global problem. The rate of development and introduction of new antibiotics for clinical use lags behind the spread of antibiotic resistance (Theuretzbacher et al, 2020). Domains of the ribosomal S1 protein from E. coli (six domains — 557 amino acid residues), T. thermophilus (five domains — 536 amino acid residues), and P. aeruginosa (six domains — 559 amino acid residues) were analyzed to select regions of the amino acid sequence of the protein potentially possessing amyloidogenic and antimicrobial properties The ribosomal S1 protein of E. coli, T. thermophilus, and P. aeruginosa contains amyloidogenic sequences that can lead to aggregation of peptide molecules with each other or with other proteins that have aggregation sites (directed coaggregation mechanism). The antibacterial effect of peptides prone to aggregation and formation of fibrils based on the amino acid sequence of the ribosomal S1 protein from E. coli did not show such success as for T. thermophilus. Human fibroblast cell survival was 70% for the peptides from T. thermophilus (Kurpe et al, 2020) and 100% for the peptides from P. aeruginosa (Supplementary Figure S4) in the peptide concentration range of 0.01–20 μg/ml (7.6 μM), which overlaps with the MIC concentration for the R23L peptide
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