Recent Antimicrobial Developments Targeting Peptidyl-tRNA Hydrolases - Abstract
Peptidyl-tRNA hydrolases (Pths) are essential enzymes found in bacteria, archaea, and eukaryotes. Pths cleave the peptide:tRNA ester bond of peptidyl-tRNAs generated
from premature termination of protein synthesis and the expression of short ORFs or minigenes. Accumulation of peptidyl-tRNAs is toxic presumably due to impaired translational initiation or slowed protein synthesis caused by specific tRNA starvation. Pth activity is thus vital for cells to deal with the build-up of peptidyl-tRNAs.
Bacterial genomes encode a highly conserved peptidyl-tRNA hydrolase enzyme, Pth1. Amino acid sequence homology is high across all species and active site residues are strictly conserved. Structures of Pth1 have been solved for several species and catalytically important residues identified. Studies with mini- and partial-substrates have contributed to understanding of substrate recognition. However, the mechanism of action and ability to distinguish between aminoacyl- and peptidyl-tRNAs are not fully understood.
Better understanding of this fundamental biological enzyme has contributed to pharmacological development against this promising new antibacterial target. Expediting the time consuming northern blot assay has paved the way for moderate screening efforts and identification of inhibitory natural product extracts. Computational small molecule docking has also provided initial insight. Overall, Pth1 is a promising new antibacterial target and continued characterization will advance antibiotic development.