S. aureus RnpA is an essential protein that displays limited amino acid sequence similarity to human proteins, suggesting that it may be an attractive antimicrobial target. The protein’s essentiality has been predicted to be governed by its function to catalyze the removal of 5’ leader sequences from precursor tRNA (ptRNA) species and thus is required for protein translation. RnpA is also associated with the organism’s mRNA degradosome holoenzyme complex and has been found to modulate cellular mRNA turnover. This raises the possibility that the protein’s essentiality in S. aureus may also be attributable to its ability to degrade mRNA transcripts, which guards against the production of unneeded/toxic protein levels while generating ribonucleoside substrates for new RNA synthesis.
S. aureus RnpA pathway may represent a novel dual functional antimicrobial target. Furthermore, resistance to corresponding small molecule RnpA inhibitors may be slow to develop because target site mutations that limit inhibitor binding may be functional for one activity (i.e., ptRNA processing) but not tolerated by the other (i.e., mRNA degradation). In our laboratory, we are identifying and characterizing (in-vitro and in-vivo) novel chemical classes of inhibitors of the essential S. aureus protein, RnpA, using a medicinal chemistry based approach that allows development of agents with on-target antimicrobial effects.
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