Identification of Bacteria-Selective Threonyl-tRNA Synthetase Substrate Inhibitors by Structure-Based Design

• Published in: Journal of medicinal chemistry Vol. 56; no. 4; pp. 1748 - 1760
• Main Authors: Teng, Min, Hilgers, Mark T, Cunningham, Mark L, Borchardt, Allen, Locke, Jeffrey B, Abraham, Sunny, Haley, Gregory, Kwan, Bryan P, Hall, Courtney, Hough, Grayson W, Shaw, Karen J, Finn, John
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 28.02.2013; Amer Chemical Soc
• Subjects: Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Bacterial Proteins - antagonists & inhibitors; Bacterial Proteins - chemistry; Binding Sites; Burkholderia - drug effects; Chemistry, Medicinal; Crystallography, X-Ray; Drug Resistance, Bacterial; Escherichia coli - drug effects; Escherichia coli - genetics; Escherichia coli Proteins - antagonists & inhibitors; Escherichia coli Proteins - chemistry; Haemophilus influenzae - drug effects; Humans; Life Sciences & Biomedicine; Microbial Sensitivity Tests; Models, Molecular; Molecular Structure; Mutation; Pharmacology & Pharmacy; Protein Binding; Quinazolines - chemical synthesis; Quinazolines - chemistry; Quinazolines - pharmacology; Science & Technology; Stereoisomerism; Structure-Activity Relationship; Substrate Specificity; Threonine-tRNA Ligase - antagonists & inhibitors; Threonine-tRNA Ligase - chemistry; Yersinia pestis - drug effects; ADENYLATE; POTENT; SERIES; MECHANISM; GENE; ANALOGS; BORRELIDIN
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm301756m

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.