Discovery and optimisation of potent, selective, ethanolamine inhibitors of bacterial phenylalanyl tRNA synthetase.
High throughput screening of Staphylococcus aureus phenylalanyl tRNA synthetase (FRS) identified ethanolamine 1 as a sub-micromolar hit. Optimisation studies led to the enantiospecific lead 64, a single-figure nanomolar inhibitor. The inhibitor series shows selectivity with respect to the mammalian enzyme and the potential for broad spectrum bacterial FRS inhibition.
Jarvest
Richard L
RL
GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK. richard.l.jarvest@gsk.com
Erskine
Symon G
SG
Forrest
Andrew K
AK
Fosberry
Andrew P
AP
Hibbs
Martin J
MJ
Jones
Joanna J
JJ
O'Hanlon
Peter J
PJ
Sheppard
Robert J
RJ
Worby
Angela
A
D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D004983:Ethanolamines / Q000138:chemical synthesis* / Q000494:pharmacology*; D007700:Kinetics; D008322:Mammals; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D010652:Phenylalanine-tRNA Ligase / Q000037:antagonists & inhibitors*; D012680:Sensitivity and Specificity; D013211:Staphylococcus aureus / Q000187:drug effects / Q000201:enzymology*; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D004983:Ethanolamines; D010652:Phenylalanine-tRNA Ligase