Antibiotic resistance prevents successful treatment of bacterial infections, making it certain that novel target locations are required to resolve this ongoing issue. The bacterial ribosome is an important target for antibacterials due to its essential contribution toward cell vitality. This work focuses on a region of the ribosome called helix 69 (H69), an RNA that is not currently a primary target of antibiotics. Helix 69 has been implicated to have important roles in ribosomal processes such as subunit association, ribosomal recycling, and tRNA selection. Conserved across phylogeny, bacterial H69 also contains three pseudouridine residues. A heptameric peptide sequence that selectively targets pseudouridylated H69 was recently identified. Solid-phase synthesis combined with electrospray ionization mass spectrometry was used to identify peptides with higher affinity and selectivity for the target RNA than the parent peptide. Apparent dissociation constants of the RNA-peptide complexes were determined. Based on these results, peptide libraries are being generated and screened using high-throughput techniques for improved ligands. This work demonstrates that new ligands targeting specific pseudouridine-containing rRNAs can be obtained, and improvements to their binding can be achieved through chemical modifications.

Development and screening of peptide ligands that target H69 of the bacterial ribosome

247th National Meeting (2014)

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