Kinetics of macrolide action: the josamycin and erythromycin cases

The Journal of Biological Chemistry
Martin LovmarMåns Ehrenberg

Abstract

Members of the macrolide class of antibiotics inhibit peptide elongation on the ribosome by binding close to the peptidyltransferase center and blocking the peptide exit tunnel in the large ribosomal subunit. We have studied the modes of action of the macrolides josamycin, with a 16-membered lactone ring, and erythromycin, with a 14-membered lactone ring, in a cell-free mRNA translation system with pure components from Escherichia coli. We have found that the average lifetime on the ribosome is 3 h for josamycin and less than 2 min for erythromycin and that the dissociation constants for josamycin and erythromycin binding to the ribosome are 5.5 and 11 nM, respectively. Josamycin slows down formation of the first peptide bond of a nascent peptide in an amino acid-dependent way and completely inhibits formation of the second or third peptide bond, depending on peptide sequence. Erythromycin allows formation of longer peptide chains before the onset of inhibition. Both drugs stimulate the rate constants for drop-off of peptidyl-tRNA from the ribosome. In the josamycin case, drop-off is much faster than drug dissociation, whereas these rate constants are comparable in the erythromycin case. Therefore, at a saturating drug concentr...Continue Reading

References

Jul 1, 1979·Proceedings of the National Academy of Sciences of the United States of America·P C Jelenc, C G Kurland
Apr 15, 1977·European Journal of Biochemistry·A Contreras, D Vázquez
Jul 1, 1975·Proceedings of the National Academy of Sciences of the United States of America·T Otaka, A Kaji
Aug 1, 1987·Biochimie·S Andersson, C G Kurland
Nov 10, 1988·Biochimica Et Biophysica Acta·G ChinaliC Cocito
May 25, 1971·Biochemistry·J C Mao, E E Robishaw
Apr 1, 1995·Antimicrobial Agents and Chemotherapy·B Weisblum
Apr 1, 1996·Archives of Biochemistry and Biophysics·M Y Pavlov, M Ehrenberg
Feb 4, 1997·Proceedings of the National Academy of Sciences of the United States of America·L L RandallM Ehrenberg
Feb 27, 1999·Journal of Bacteriology·T TensonA S Mankin
Jun 3, 2000·The EMBO Journal·V Heurgué-HamardM Ehrenberg
Mar 15, 2002·Cell·Tanel Tenson, Måns Ehrenberg
Mar 23, 2002·Cell·V Ramakrishnan
Jul 12, 2002·Nature·Peter B Moore, Thomas A Steitz
Aug 2, 2002·Molecular Cell·Jeffrey L HansenThomas A Steitz
Mar 8, 2003·Structure·Frank SchlünzenAda Yonath
Apr 1, 2003·Nature Structural Biology·Rita BerisioAda Yonath
Jul 3, 2003·Journal of Bacteriology·Rita BerisioAda Yonath

❮ Previous
Next ❯

Citations

Nov 19, 2008·Proceedings of the National Academy of Sciences of the United States of America·Sean D Moore, Robert T Sauer
Mar 1, 2012·Nucleic Acids Research·Ourania N KostopoulouDimitrios L Kalpaxis
Jan 24, 2009·Antimicrobial Agents and Chemotherapy·Ekaterini C KouvelaGeorge P Dinos
Jan 16, 2013·Antimicrobial Agents and Chemotherapy·Julia GödekeSusanne Häussler
Mar 26, 2015·Journal of Enzyme Inhibition and Medicinal Chemistry·Marios KrokidisGeorge P Dinos
Mar 12, 2010·International Journal of Antimicrobial Agents·April BarbourHartmut Derendorf
Dec 17, 2008·Journal of Molecular Biology·Alexandros D PetropoulosDimitrios L Kalpaxis
Jan 28, 2009·Molecular Microbiology·Haripriya RamuNora Vazquez-Laslop
Mar 24, 2006·Molecular Microbiology·Tanel Tenson, Alexander Mankin
Mar 26, 2016·Frontiers in Microbiology·Hao TanWeihui Wu
Dec 24, 2011·Annals of the New York Academy of Sciences·Krishna Kannan, Alexander S Mankin
Sep 23, 2008·Current Opinion in Microbiology·Alexander S Mankin
Apr 29, 2008·Molecular Cell·Nora Vazquez-LaslopAlexander S Mankin
Jun 19, 2014·Nucleic Acids Research·Ourania N KostopoulouDimitrios L Kalpaxis
Mar 29, 2014·ACS Chemical Biology·Jinfan WangAnthony C Forster
Jul 11, 2006·The Journal of Biological Chemistry·Amanda RaineMåns Ehrenberg
Dec 15, 2007·The Journal of Biological Chemistry·Alexandros D PetropoulosDimitrios L Kalpaxis
Jan 18, 2006·The Journal of Biological Chemistry·Martin LovmarMåns Ehrenberg
Jul 29, 2018·Trends in Biochemical Sciences·Nora Vázquez-Laslop, Alexander S Mankin
Mar 22, 2021·Journal of Molecular Biology·A Carolin SeefeldtMagnus Johansson
Apr 3, 2021·Frontiers in Microbiology·Anne-Gaëlle LeroyLise Crémet
May 28, 2009·Journal of Chemical Information and Modeling·Wai Keat Yam, Habibah A Wahab
Apr 17, 2008·Biochemistry·Peter J Tummino, Robert A Copeland
Aug 19, 2020·Current Drug Metabolism·Liyun ZhangYanfei Tao

❮ Previous
Next ❯

Related Concepts

Related Feeds

Antifungals

An antifungal, also known as an antimycotic medication, is a pharmaceutical fungicide or fungistatic used to treat and prevent mycosis such as athlete's foot, ringworm, candidiasis, cryptococcal meningitis, and others. Discover the latest research on antifungals here.

ASBMB Publications

The American Society for Biochemistry and Molecular Biology (ASBMB) includes the Journal of Biological Chemistry, Molecular & Cellular Proteomics, and the Journal of Lipid Research. Discover the latest research from ASBMB here.

Antifungals (ASM)

An antifungal, also known as an antimycotic medication, is a pharmaceutical fungicide or fungistatic used to treat and prevent mycosis such as athlete's foot, ringworm, candidiasis, cryptococcal meningitis, and others. Discover the latest research on antifungals here.