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Chloramphenicol (CAM) inhibits peptide bond formation by binding to the 50S subunit of prokaryotic ribosomes and interfering competitively with the binding of the aminoacyl-tRNA 3'- terminus to ribosomal A-site. Further studies have demonstrated that CAM (I) reacts rapidly with a model initiator ribosomal complex (poly(U)-programmed ribosomes from Escherichia coli, bearing AcPhe-tRNA at the P-site), complex C, to form an encounter complex CI which is then isomerized slowly to a tighter complex, C  I. Herein, we show by time-resolved footprinting analysis that CAM produces a footprint in CI complex, comprising nucleotides A2451, G2505, and U2506, all exhibiting reduced reactivity against base-specific modifying agents. When C  I complex is footprinted, the reactivities of G2505 and U2506 are almost restored, while protection is observed at A2062 and altered reactivity at A2058 and A2059. Our results suggest that CAM initially binds to a hydrophobic crevice composed of nucleotides located adjacently to the A-site (CI complex). Soon after, CAM shifts slowly to a final position, in which the interaction between the p-nitrobenzyl group of CAM and the base of A2451 is conserved, while the dichloroacetyl group reorientates toward A2062. Analogous behavior is observed, if CAM is modified by replacement of dichloroacetyl group with  -alanyl. However, insertion at this position of a bulkier group, such as phenylalanyl-phenylalanyl group, sterically prevents CAM accommodation to its initial binding site and favors its direct fitting into the final binding pocket. Our data correlate well with recent crystallographic results regarding CAM binding on Thermus thermophilus and E. coli ribosomes.

Insights into the Chloramphenicol Inhibition Effect on Peptidyl Transferase Activity, Using Two New Analogs of the Drug