title: The structure of ribosome-lankacidin complex reveals ribosomal sites for synergistic antibiotics.
abstract: Crystallographic analysis revealed that the 17-member polyketide antibiotic lankacidin produced by Streptomyces rochei binds at the peptidyl transferase center of the eubacterial large ribosomal subunit. Biochemical and functional studies verified this finding and showed interference with peptide bond formation. Chemical probing indicated that the macrolide lankamycin, a second antibiotic produced by the same species, binds at a neighboring site, at the ribosome exit tunnel. These two antibiotics can bind to the ribosome simultaneously and display synergy in inhibiting bacterial growth. The binding site of lankacidin and lankamycin partially overlap with the binding site of another pair of synergistic antibiotics, the streptogramins. Thus, at least two pairs of structurally dissimilar compounds have been selected in the course of evolution to act synergistically by targeting neighboring sites in the ribosome. These results underscore the importance of the corresponding ribosomal sites for development of clinically relevant synergistic antibiotics and demonstrate the utility of structural analysis for providing new directions for drug discovery.
authors.affiliation: Department of Structural Biology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Tamar
authors.initials: T
authors.lastname: Auerbach
authors.forename: Inbal
authors.initials: I
authors.lastname: Mermershtain
authors.forename: Chen
authors.initials: C
authors.lastname: Davidovich
authors.forename: Anat
authors.initials: A
authors.lastname: Bashan
authors.forename: Matthew
authors.initials: M
authors.lastname: Belousoff
authors.forename: Itai
authors.initials: I
authors.lastname: Wekselman
authors.forename: Ella
authors.initials: E
authors.lastname: Zimmerman
authors.forename: Liqun
authors.initials: L
authors.lastname: Xiong
authors.forename: Dorota
authors.initials: D
authors.lastname: Klepacki
authors.forename: Kenji
authors.initials: K
authors.lastname: Arakawa
authors.forename: Haruyasu
authors.initials: H
authors.lastname: Kinashi
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Mankin
authors.forename: Ada
authors.initials: A
authors.lastname: Yonath
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000378:metabolism*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D034301:Deinococcus / Q000737:chemistry / Q000378:metabolism; D055808:Drug Discovery; D004357:Drug Synergism; D004917:Erythromycin / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D018942:Macrolides / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D015394:Molecular Structure; D054681:Ribosome Subunits, Large, Bacterial / Q000737:chemistry / Q000378:metabolism; D012270:Ribosomes / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D018942:Macrolides; C008250:lankacidins; D004917:Erythromycin; C100149:kujimycin B