title: A click chemistry approach to pleuromutilin derivatives, part 2: conjugates with acyclic nucleosides and their ribosomal binding and antibacterial activity.
abstract: Pleuromutilin is an antibiotic that binds to bacterial ribosomes and thereby inhibit protein synthesis. A new series of semisynthetic pleuromutilin derivatives were synthesized by a click chemistry strategy. Pleuromutilin was conjugated by different linkers to a nucleobase, nucleoside, or phenyl group, as a side-chain extension at the C22 position of pleuromutilin. The linkers were designed on the basis of the best linker from our first series of pleuromutilin derivatives following either conformational restriction or an isosteric methylene to oxygen exchange. The binding of the new compounds to the  Escherichia coli  ribosome was investigated by molecular modeling and chemical footprinting of nucleotide U2506, and it was found that all the derivatives bind to the specific site and most of them better than pleuromutilin itself. The effect of the side-chain extension was also explored by chemical footprinting of nucleotide U2585, and the results showed that all the compounds interact with this position to varying degrees. Derivatives with a conformational restriction of the linker generally had a higher affinity than derivatives with an isosteric exchange of one of the carbons in the linker with a hydrophilic oxygen. A growth inhibition assay with three different bacterial strains showed significant activity of several of the new compounds.
authors.affiliation: Nucleic Acid Center, University of Southern Denmark, 5230 Odense M, Denmark.
authors.forename: Ida
authors.initials: I
authors.lastname: Dreier
authors.forename: Surender
authors.initials: S
authors.lastname: Kumar
authors.forename: Helle
authors.initials: H
authors.lastname: Søndergaard
authors.forename: Maria Louise
authors.initials: ML
authors.lastname: Rasmussen
authors.forename: Lykke Haastrup
authors.initials: LH
authors.lastname: Hansen
authors.forename: Nanna Holmgaard
authors.initials: NH
authors.lastname: List
authors.forename: Jacob
authors.initials: J
authors.lastname: Kongsted
authors.forename: Birte
authors.initials: B
authors.lastname: Vester
authors.forename: Poul
authors.initials: P
authors.lastname: Nielsen
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001412:Bacillus subtilis / Q000187:drug effects; D001665:Binding Sites; D057930:Click Chemistry; D004224:Diterpenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004926:Escherichia coli / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D008087:Listeria / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D008968:Molecular Conformation; D009705:Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010458:Peptidyl Transferases / Q000378:metabolism; D011083:Polycyclic Compounds; D012329:RNA, Bacterial / Q000378:metabolism; D012338:RNA, Ribosomal, 23S / Q000378:metabolism; D012270:Ribosomes / Q000187:drug effects / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D000097567:Pleuromutilins
chemical_list: D000900:Anti-Bacterial Agents; D004224:Diterpenes; D009705:Nucleosides; D010458:Peptidyl Transferases; D011083:Polycyclic Compounds; D012329:RNA, Bacterial; D012338:RNA, Ribosomal, 23S; D000097567:Pleuromutilins