Poster abstracts
Poster number 160 submitted by Teresa Wolak
RNA-targeting antibiotic peptides: a multi-pronged approach
Teresa Wolak (Wayne State University), Rabiul Islam (Wayne State University), Hien M. Nguyen (Wayne State University), Christine S. Chow (Wayne State University)
Abstract:
The expanding scope of antibiotic-resistant pathogens stresses an urgency to develop unexploited classes of antibiotic compounds. Proline-rich antimicrobial peptides (PrAMPs) target translating ribosomes but differ from conventional antibiotics in their mechanisms of action. PrAMPs arrest translation by binding to the peptidyl transferase center and inhibit nascent peptide production by blocking or trapping ribosomal substrates. To further enhance antibiotic activity, we employed a plasmid-based antibiotic peptide expression system to evaluate mutants of the PrAMP oncocin. Antibacterial activity of the mutants was determined in Escherichia coli and verified with a minimum inhibitory concentration (MIC) assay. Mechanistic and structural impacts of the oncocin mutants were evaluated with molecular modeling. Structural and sequence alignments were performed on available PrAMP-ribosome crystal structures and bacterial 23S rRNA, respectively. Alignment of Type I PrAMPs revealed similarities in N-terminal residues with respect to ribosomal binding region and peptide secondary structure. Sequence alignment of over 1,000 bacterial species 23S rRNA was visualized in 3D to reveal globally conserved regions that bind directly with PrAMPs or other translation factors. Herein, we are using a multidisciplinary approach to streamline the drug development process by direct evaluation of structure-function relationships, gain insights to further develop PrAMPs as antibiotics, and identify conserved regions of bacterial 23S rRNA that will aid in development into rRNA-targeting therapeutics.
Keywords: antibiotic peptides, rRNA-targeting, multidisciplinary