期刊
NATURE CHEMICAL BIOLOGY
卷 13, 期 10, 页码 1129-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/NCHEMBIO.2462
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资金
- National Institute of General Medical Sciences, US National Institutes of Health [P41 GM103403]
- NIH-ORIP HEI [S10 RR029205]
- DOE Office of Science [DE-AC02-06CH11357]
- Illinois State startup funds
- US National Institutes of Health [R01 AI117210]
- Skoltech Institutional funds
- Russian Foundation for Basic Research [16-04-01100, 15-34-20139]
- Ministry of Education and Science of the Russian Federation [14.B25.31.0004]
- Russian Science Foundation [15-15-10017]
- Dynasty Foundation
- FASIE [9186GU/2015]
- [14-14-00072]
- Russian Science Foundation [15-15-10017, 14-14-00072, 17-14-00014] Funding Source: Russian Science Foundation
Whereas screening of the small-molecule metabolites produced by most cultivatable microorganisms often results in the rediscovery of known compounds, genome-mining programs allow researchers to harness much greater chemical diversity, and result in the discovery of new molecular scaffolds. Here we report the genome-guided identification of a new antibiotic, klebsazolicin (KLB), from Klebsiella pneumoniae that inhibits the growth of sensitive cells by targeting ribosomes. A ribosomally synthesized post-translationally modified peptide (RiPP), KLB is characterized by the presence of a unique N-terminal amidine ring that is essential for its activity. Biochemical in vitro studies indicate that KLB inhibits ribosomes by interfering with translation elongation. Structural analysis of the ribosome-KLB complex showed that the compound binds in the peptide exit tunnel overlapping with the binding sites of macrolides or streptogramin-B. KLB adopts a compact conformation and largely obstructs the tunnel. Engineered KLB fragments were observed to retain in vitro activity, and thus have the potential to serve as a starting point for the development of new bioactive compounds.
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