title: Structural basis for the antibiotic activity of ketolides and azalides.
abstract: The azalide azithromycin and the ketolide ABT-773, which were derived by chemical modifications of erythromycin, exhibit elevated activity against a number of penicillin- and macrolide-resistant pathogenic bacteria. Analysis of the crystal structures of the large ribosomal subunit from Deinococcus radiodurans complexed with azithromycin or ABT-773 indicates that, despite differences in the number and nature of their contacts with the ribosome, both compounds exert their antimicrobial activity by blocking the protein exit tunnel. In contrast to all macrolides studied so far, two molecules of azithromycin bind simultaneously to the tunnel. The additional molecule also interacts with two proteins, L4 and L22, implicated in macrolide resistance. These studies illuminated and rationalized the enhanced activity of the drugs against specific macrolide-resistant bacteria.
authors.affiliation: Max-Planck-Research Unit for Ribosomal Structure, 22603, Hamburg, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Schlünzen
authors.forename: Jörg M
authors.initials: JM
authors.lastname: Harms
authors.forename: Francois
authors.initials: F
authors.lastname: Franceschi
authors.forename: Harly A S
authors.initials: HA
authors.lastname: Hansen
authors.forename: Heike
authors.initials: H
authors.lastname: Bartels
authors.forename: Raz
authors.initials: R
authors.lastname: Zarivach
authors.forename: Ada
authors.initials: A
authors.lastname: Yonath
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000378:metabolism; D017963:Azithromycin / Q000737:chemistry* / Q000378:metabolism; D004917:Erythromycin / Q000031:analogs & derivatives / Q000737:chemistry* / Q000378:metabolism; D048628:Ketolides; D012335:RNA, Ribosomal; D012270:Ribosomes / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D048628:Ketolides; D012335:RNA, Ribosomal; D004917:Erythromycin; D017963:Azithromycin; C405499:cethromycin