New inhibitors of bacterial protein synthesis from a combinatorial library of macrocycles

A mixture-based combinatorial. library of 14-membered macrocycles was synthesized to target ribosomal RNA and uncover a new class of antibacterial agents. High-throughput screening identified a macrocyclic mixture that inhibited cell-free-coupled transcription/translation in Escherichia coli-derived extracts, with an IC50 value in the 25-50 muM range. In a follow-up library of 64 single macrocycles, 8 gave IC50 values ranging from 12 to 50 muM in the cell-free protein synthesis inhibition assay. Some of the macrocycles were screened in a translation inhibition assay, and IC50 values generally paralleled those obtained in the uncoupled transcription/translation assay. Additional analogues were prepared in a preliminary structure-activity relationship study, and more potent macrocycles were identified with low micromolar activity (IC50 values = 2-3 muM). Some of these macrocycles displayed antibacterial activity against lipopolysaccharide mutant E. coli bacterial cells (IC50 values = 12-50 muM).