Chloramphenicol (CAM) binds to the bacterial 50S ribosomal subunit and inhibits the peptide bond forming reaction catalyzed by the peptidyltransferase active site. High-resolution crystal structures of the ribosome have revealed that the CAM binding site is deep within the 50S subunit in a structure composed almost exclusively of rRNA. Computational docking leads us to predict that binding can be further improved with changes to certain CAM functional groups. Individual modifications can potentially either enhance or impair binding, and both can be informative with regard to the nature of drug-ribosome interactions. Here we describe derivatives of CAM and their inhibitory activity against the bacterium <i>Thermus thermophilus</i>, a model system for ribosome structural studies. We also report their activity against a number of CAM-resistant mutants of <i>T. thermophilus</i> with base substitutions in the CAM binding site.

Synthesis of novel chloramphenicol derivatives as ribosome-targeting antibiotics

256th National Meeting (2018)

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