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Exploring Amyloidogenicity of Peptides From Ribosomal S1 Protein to Develop Novel AMPs.

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.

SUBMITTER: Galzitskaya OV

PROVIDER: S-EPMC8416663 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Resistance to key first-line drugs is a major hurdle to achieve the global end tuberculosis (TB) targets. A prodrug, pyrazinamide (PZA) is the only drug, effective in latent TB, recommended in drug resistance and susceptible Mycobacterium tuberculosis (MTB) isolates. The prodrug conversion into active form, pyrazinoic acid (POA), required the activity of pncA gene encoded pyrazinamidase (PZase). Although pncA mutations have been commonly associated with PZA resistance but a small number of resistance cases have been associated with mutationss in RpsA protein. Here in this study a total of 69 PZA resistance isolates have been sequenced for pncA mutations. However, samples that were found PZA resistant but pncA wild type (pncAWT), have been sequenced for rpsA and panD genes mutation. We repeated a drug susceptibility testing according to the WHO guidelines on 18 pncAWT MTB isolates. The rpsA and panD genes were sequenced. Out of total 69 PZA resistant isolates, 51 harbored 36 mutations in pncA gene (GeneBank Accession No. MH46111) while, fifteen different mutations including seven novel, were detected in the fourth S1 domain of RpsA known as C-terminal (MtRpsACTD) end. We did not detect any mutations in panD gene. Among the rpsA mutations, we investigated the molecular mechanism of resistance behind mutations, D342N, D343N, A344P, and I351F, present in the MtRpsACTD through molecular dynamic simulations (MD). WT showed a good drug binding affinity as compared to mutants (MTs), D342N, D343N, A344P, and I351F. Binding pocket volume, stability, and fluctuations have been altered whereas the total energy, protein folding, and geometric shape analysis further explored a significant variation between WT and MTs. In conclusion, mutations in MtRpsACTD might be involved to alter the RpsA activity, resulting in drug resistance. Such molecular mechanism behind resistance may provide a better insight into the resistance mechanism to achieve the global TB control targets.

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Exploring Amyloidogenicity of Peptides From Ribosomal S1 Protein to Develop Novel AMPs.

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