Structure-Guided Enhancement of Selectivity of Chemical Probe Inhibitors Targeting Bacterial Seryl-tRNA Synthetase

  • J Med Chem. 2019 Nov 14;62(21):9703-9717. doi: 10.1021/acs.jmedchem.9b01131.
Ricky Cain  1 ,  Ramya Salimraj  1 ,  Avinash S Punekar  1 ,  Dom Bellini  1 ,  Colin W G Fishwick  2 ,  Lloyd Czaplewski  3 ,  David J Scott  4  5 ,  Gemma Harris  5 ,  Christopher G Dowson  1 ,  Adrian J Lloyd  1 ,  David I Roper  1
Affiliations
  • 1. School of Life Sciences , University of Warwick , Gibbet Hill Road , Coventry CV4 7AL , United Kingdom.
  • 2. School of Chemistry , University of Leeds , Leeds LS2 9JT , United Kingdom.
  • 3. Chemical Biology Ventures Limited , Abingdon OX14 1XD , United Kingdom.
  • 4. School of Biosciences , University of Nottingham , Nottingham LE12 5RD , United Kingdom.
  • 5. ISIS Spallation Neutron and Muon Source and the Research Complex at Harwell , Rutherford Appleton Laboratory , Oxfordshire OX11 0FA , United Kingdom.
PMID: 31626547 DOI: 10.1021/acs.jmedchem.9b01131
Abstract

Aminoacyl-tRNA synthetases are ubiquitous and essential Enzymes for protein synthesis and also a variety of Other metabolic processes, especially in Bacterial species. Bacterial aminoacyl-tRNA synthetases represent attractive and validated targets for antimicrobial drug discovery if issues of prokaryotic versus eukaryotic selectivity and Antibiotic resistance generation can be addressed. We have determined high-resolution X-ray crystal structures of the Escherichia coli and Staphylococcus aureus seryl-tRNA synthetases in complex with aminoacyl adenylate analogues and applied a structure-based drug discovery approach to explore and identify a series of small molecule inhibitors that selectively inhibit Bacterial seryl-tRNA synthetases with greater than 2 orders of magnitude compared to their human homologue, demonstrating a route to the selective chemical inhibition of these Bacterial targets.

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