ИСТИНА

While screening of small-molecular metabolites produced by most cultivatable microorganisms often results in rediscovery of known compounds, genome-mining programs allow to harness much greater chemical diversity and result in discovery of new molecular scaffolds. Here we report genome-guided identification of a new antibiotic klebsazolicin (KLB) that inhibits growth of sensitive cells by interfering with protein synthesis by targeting ribosome. A member of the linear azol(in)e-containing peptides (LAPs), KLB is characterized by the presence of the unique N-terminal amidine ring essential for its activity. Biochemical in vitro studies indicate that KLB inhibits ribosome by interfering with the early stages of translation elongation. Structural analysis of the ribosome in complex with KLB shows that the compound binds in the nascent peptide exit tunnel in a site, which overlaps but is not identical to the binding site of macrolides or streptogramins B. The compact KLB molecule almost completely obstructs the tunnel. Engineered KLB fragments retain in vitro activity and can serve as a starting point for the development of a new family of bioactive compounds.