Antibiotic chloramphenicol (CLM) 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 analogues of CLM. The L-histidyl analogue binds to the ribosome with the affinity exceeding that of CLM by 10 fold. Several of the newly synthesized analogues were able to inhibit protein synthesis and exhibited the mode of action that was distinct from the action of CLM. However, the inhibitory properties of the semi-synthetic CLM-analogues did not correlate with their affinity and in general, the amino-acid analogues of CLM 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 analogues showed that CLM 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.

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