Abstract

A significant number of antibiotics inhibit protein synthesis through blockade of the peptidyl-transferase site on the ribosome. In order to rationalize observed similarities in the mode of action, we have compared structural features of ten peptidyl-transferase inhibitors: amicetin, blasticidin S, chloramphenicol, erythromycin, gougerotin, lincomycin, oleandomycin, pleuromutilin, puromycin, and sparsomycin. Conformational analyses were carried out using the Duchamp molecular mechanics procedure, and structural comparisons were made through computer-aided superposition of structures. As a result of the investigation, we found several key features required for recognition of the catalytic center for ribosomal peptide bond formation. The binding model has been tested successfully by the synthesis of a novel agent, quantamycin, which has affinity for the peptidyl-transferase site.

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