Structural basis for the antibiotic activity of ketolides and azalides

Schlunzen, Frank; Harms, Joerg M.; Franceschi, Francois; Hansen, Harly A. S.; Bartels, Heike; Zarivach, Raz; Yonath, Ada

doi:10.1016/S0969-2126(03)00022-4

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Structural basis for the antibiotic activity of ketolides and azalides

MPS-Authors

Schlunzen, Frank
Max Planck Society;

Harms, Joerg M.
Max Planck Society;

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Franceschi, Francois
Ribosomes, Max Planck Institute for Molecular Genetics, Max Planck Society;

Hansen, Harly A. S.
Max Planck Society;

Bartels, Heike
Max Planck Society;

Zarivach, Raz
Max Planck Society;

Yonath, Ada
Max Planck Society;

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Citation

Schlunzen, F., Harms, J. M., Franceschi, F., Hansen, H. A. S., Bartels, H., Zarivach, R., et al. (2003). Structural basis for the antibiotic activity of ketolides and azalides. Structure, 11(3), 329-338. doi:10.1016/S0969-2126(03)00022-4.

Cite as: https://hdl.handle.net/11858/00-001M-0000-0010-8AA8-5

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