Binding and Action of Amino Acid Analogs of Chloramphenicol upon the Bacterial Ribosome. Issue 6 (16th March 2018)

• Record Type: Journal Article
• Authors: Tereshchenkov, Andrey G.; Dobosz-Bartoszek, Malgorzata; Osterman, Ilya A.; Marks, James; Sergeeva, Vasilina A.; Kasatsky, Pavel; Komarova, Ekaterina S.; Stavrianidi, Andrey N.; Rodin, Igor A.; Konevega, Andrey L.; Sergiev, Petr V.; Sumbatyan, Natalia V.; Mankin, Alexander S.; Bogdanov, Alexey A.; Polikanov, Yury S.
• Is Part Of: Journal of molecular biology. Volume 430:Issue 6(2018)
• Page Start: 842
• Page End: 852
• Publication Date: 2018-03-16
• Subjects: antibiotic -- ribosome -- X-ray structure -- protein synthesis -- peptidyl transferase center; CHL chloramphenicol -- AA-CAMs aminoacyl-CAM -- PTC peptidyl transferase center -- aa-tRNA aminoacyl-tRNA -- NPET nascent peptide exit tunnel -- BODIPY-ERY BODIPY-labeled erythromycin -- ORF open reading frame -- PY protein Y -- H-bond hydrogen bond -- Tth Thermus thermophilus; Molecular biology -- Periodicals; Biology -- Periodicals; Biochemistry -- Periodicals; Bacteriology -- Periodicals; Molecular Biology -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biologie -- Périodiques; Biochimie -- Périodiques; Moleculaire biologie; Biochemistry; Biology; Molecular biology; Periodicals; 572.805
• DOI: 10.1016/j.jmb.2018.01.016
• Languages: English
• ISSNs: 0022-2836

Abstract

Abstract: Antibiotic chloramphenicol (CHL) binds with a moderate affinity at the peptidyl transferase center of the bacterial ribosome and inhibits peptide bond formation. As an approach for modifying and potentially improving properties of this inhibitor, we explored ribosome binding and inhibitory activity of a number of amino acid analogs of CHL. The L-histidyl analog binds to the ribosome with the affinity exceeding that of CHL by 10 fold. Several of the newly synthesized analogs were able to inhibit protein synthesis and exhibited the mode of action that was distinct from the action of CHL. However, the inhibitory properties of the semi-synthetic CHL analogs did not correlate with their affinity and in general, the amino acid analogs of CHL were less active inhibitors of translation in comparison with the original antibiotic. The X-ray crystal structures of the Thermus thermophilus 70S ribosome in complex with three semi-synthetic analogs showed that CHL derivatives bind at the peptidyl transferase center, where the aminoacyl moiety of the tested compounds established idiosyncratic interactions with rRNA. Although still fairly inefficient inhibitors of translation, the synthesized compounds represent promising chemical scaffolds that target the peptidyl transferase center of the ribosome and potentially are suitable for further exploration. Graphical Abstract: Highlights: Aminoacyl derivatives of the antibiotic chloramphenicol (AA-CAMs) can bind to the peptidyl transferase center of the bacterial ribosome with better affinities than the parent compound. AA-CAM derivatives show different site specificity of action compared to chloramphenicol and establish compound-specific interactions with the nucleotides of the 23S rRNA. The inhibitory properties of the semi-synthetic CHL analogs do not correlate with their affinities to the vacant ribosome. AA-CAMs represent promising chemical scaffolds that target the peptidyl transferase center and the nascent peptide exit tunnel.