Identification of bacteria-selective threonyl-tRNA synthetase substrate inhibitors by structure-based design.
A series of potent and bacteria-selective threonyl-tRNA synthetase (ThrRS) inhibitors have been identified using structure-based drug design. These compounds occupied the substrate binding site of ThrRS and showed excellent binding affinities for all of the bacterial orthologues tested. Some of the compounds displayed greatly improved bacterial selectivity. Key residues responsible for potency and bacteria/human ThrRS selectivity have been identified. Antimicrobial activity has been achieved against wild-type Haemophilus influenzae and efflux-deficient mutants of Escherichia coli and Burkholderia thailandensis.
Medicinal Chemistry, Trius Therapeutics, Inc., 6310 Nancy Ridge Drive, San Diego, California 92121, United States. mteng@triusrx.com
Min
M
Teng
Mark T
MT
Hilgers
Mark L
ML
Cunningham
Allen
A
Borchardt
Jeffrey B
JB
Locke
Sunny
S
Abraham
Gregory
G
Haley
Bryan P
BP
Kwan
Courtney
C
Hall
Grayson W
GW
Hough
Karen J
KJ
Shaw
John
J
Finn
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D001665:Binding Sites; D019117:Burkholderia / Q000187:drug effects; D018360:Crystallography, X-Ray; D024881:Drug Resistance, Bacterial; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics; D029968:Escherichia coli Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D006193:Haemophilus influenzae / Q000187:drug effects; D006801:Humans; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D009154:Mutation; D011485:Protein Binding; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013914:Threonine-tRNA Ligase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D015010:Yersinia pestis / Q000187:drug effects
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D029968:Escherichia coli Proteins; D011799:Quinazolines; D013914:Threonine-tRNA Ligase