title: Elucidation of the Teixobactin Pharmacophore.
abstract: This paper elucidates the teixobactin pharmacophore by comparing the arginine analogue of teixobactin Arg10-teixobactin to seven homologues with varying structure and stereochemistry. The roles of the guanidinium group at position 10, the stereochemistry of the macrolactone ring, and the "tail" comprising residues 1-5 are investigated. The guanidinium group is not necessary for activity; Lys10-teixobactin is more active than Arg10-teixobactin against Gram-positive bacteria in minimum inhibitory concentration (MIC) assays. The relative stereochemistry of the macrolactone ring is important. Diastereomer l-Thr8,Arg10-teixobactin is inactive, and diastereomer d-allo-Ile11,Arg10-teixobactin is less active. The macrolactone ring is critical; seco-Arg10-teixobactin is inactive. The absolute stereochemistry is not important; the enantiomer ent-Arg10-teixobactin is comparable in activity. The hydrophobic N-terminal tail is important. Truncation of residues 1-5 results in loss of activity, and replacement of residues 1-5 with a dodecanoyl group partially restores activity. These findings pave the way for developing simpler homologues of teixobactin with enhanced pharmacological properties.
authors.affiliation: Department of Chemistry, University of California, Irvine , Irvine, California 92697-2025, United States.
authors.forename: Hyunjun
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Chemistry, University of California, Irvine , Irvine, California 92697-2025, United States.
authors.forename: Kevin H
authors.initials: KH
authors.lastname: Chen
authors.affiliation: Department of Chemistry, University of California, Irvine , Irvine, California 92697-2025, United States.
authors.forename: James S
authors.initials: JS
authors.lastname: Nowick
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology; D047630:Depsipeptides / Q000737:chemistry* / Q000494:pharmacology; D006094:Gram-Positive Bacteria / Q000187:drug effects; D057927:Hydrophobic and Hydrophilic Interactions; D008826:Microbial Sensitivity Tests; D013237:Stereoisomerism
chemical_list: D000900:Anti-Bacterial Agents; D047630:Depsipeptides; C000594838:teixobactin