Co-produced natural ketolides methymycin and pikromycin inhibit bacterial growth by preventing synthesis of a limited number of proteins

Antibiotics methymycin (MTM) and pikromycin (PKM), co-produced by Streptomyces venezuelae, represent minimalist macrolide protein synthesis inhibitors. Unlike other macrolides, which carry several side chains, a single desosamine sugar is attached to the macrolactone ring of MTM and PKM. In addition...

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Published in:Nucleic acids research 2017-09, Vol.45 (16), p.9573-9582
Main Authors: Almutairi, Mashal M, Svetlov, Maxim S, Hansen, Douglas A, Khabibullina, Nelli F, Klepacki, Dorota, Kang, Han-Young, Sherman, David H, Vázquez-Laslop, Nora, Polikanov, Yury S, Mankin, Alexander S
Format: Article
Language:English
Subjects:
Bacterial Proteins - biosynthesis
BASIC BIOLOGICAL SCIENCES
Binding, Competitive
Crystallography, X-Ray
Escherichia coli - drug effects
Escherichia coli - genetics
Escherichia coli - growth & development
Macrolides - chemistry
Macrolides - metabolism
Macrolides - pharmacology
Molecular Biology
Peptide Elongation Factor G - genetics
Protein Synthesis Inhibitors - pharmacology
Ribosomes - chemistry
Ribosomes - metabolism
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Summary:Antibiotics methymycin (MTM) and pikromycin (PKM), co-produced by Streptomyces venezuelae, represent minimalist macrolide protein synthesis inhibitors. Unlike other macrolides, which carry several side chains, a single desosamine sugar is attached to the macrolactone ring of MTM and PKM. In addition, the macrolactone scaffold of MTM is smaller than in other macrolides. The unusual structure of MTM and PKM and their simultaneous secretion by S. venezuelae bring about the possibility that two compounds would bind to distinct ribosomal sites. However, by combining genetic, biochemical and crystallographic studies, we demonstrate that MTM and PKM inhibit translation by binding to overlapping sites in the ribosomal exit tunnel. Strikingly, while MTM and PKM readily arrest the growth of bacteria, ∼40% of cellular proteins continue to be synthesized even at saturating concentrations of the drugs. Gel electrophoretic analysis shows that compared to other ribosomal antibiotics, MTM and PKM prevent synthesis of a smaller number of cellular polypeptides illustrating a unique mode of action of these antibiotics.
ISSN:0305-1048
1362-4962
DOI:10.1093/nar/gkx673