Protein biosynthesis is one of the fundamental processes required for all living cells, thereby making the prokaryotic ribosome one of the major targets for a large number of clinically used antimicrobial agents. Bacterial ribosome-targeting antibiotics inhibit protein synthesis by interfering with the process of messenger RNA translation or by preventing the formation of peptidic bonds. These effects result from the binding of these antibiotics to the aminoacyl-tRNA binding domain (A-site), to the peptidyltransferase domain (P-site), or to elements on both sites.
In this study, we describe the synthesis of a full set of homo- and hetero-dimers of three intact structures of different ribosome-targeting antibiotics; tobramycin, clindamycin, and chloramphenicol. Several aspects of the biological activity of the dimeric structures were evaluated including antimicrobial activity, inhibition of bacterial protein translation in vitro, and the effect of dimerization on the action of several bacterial resistance mechanisms that deactivate tobramycin and chloramphenicol. The results of this study revealed that covalently linking two identical or different ribosome-targeting antibiotics may lead to (i) a broader spectrum of antimicrobial activity compared to that of each of the parent antibiotics from which they were derived, (ii) improved bacterial translation inhibition properties, and (iii) and reduction in the efficacy of some drug-modifying enzymes that confer high levels of resistance to the parent antibiotics from which the dimers were derived from.
