Abstract
Crystallographic analysis revealed that the 17-member polyketide antibiotic lankacidin produced by Streptomyces rochei binds at the peptidyl transferase center of the eubacterial large ribosomal subunit. Biochemical and functional studies verified this finding and showed interference with peptide bond formation. Chemical probing indicated that the macrolide lankamycin, a second antibiotic produced by the same species, binds at a neighboring site, at the ribosome exit tunnel. These two antibiotics can bind to the ribosome simultaneously and display synergy in inhibiting bacterial growth. The binding site of lankacidin and lankamycin partially overlap with the binding site of another pair of synergistic antibiotics, the streptogramins. Thus, at least two pairs of structurally dissimilar compounds have been selected in the course of evolution to act synergistically by targeting neighboring sites in the ribosome. These results underscore the importance of the corresponding ribosomal sites for development of clinically relevant synergistic antibiotics and demonstrate the utility of structural analysis for providing new directions for drug discovery.
Highlights
Biochemical, genetic and functional evidence indicate that a great variety of antibiotics inhibit protein synthesis by binding to ribosomal functional regions
Lankacidin C (LC) binding pocket is composed of nucleotides A2602, C2452, A2503, U2504, G2505, U2585, G2061, and U2506 (E. coli numbering throughout), and the bound LC is involved in an extensive network of hydrophobic interactions with most of these nucleotides
Similar to pleuromutilins that utilize a network of remote interactions, LC binding is influenced by the second-shell nucleotides, G2576, A2062, C2530, U2531, C2507, U2584, G2581, C2610, and A2059
Summary
Biochemical, genetic and functional evidence indicate that a great variety of antibiotics inhibit protein synthesis by binding to ribosomal functional regions. As well as their clinically relevant semisynthetic derivatives, bind at the peptidyl transferase center (PTC) in the large ribosomal subunit [3,4,5,6,7,8,9,10,11,12,13,14] Most of these compounds inhibit cell growth by interfering with peptide bond formation [15]. The second major antibiotic binding site in the large ribosomal subunit is located at the upper segment of the nascent peptide exit tunnel (NPET), adjacent to the PTC, and is used by macrolides and type B streptogramins [3, 7, 16,17,18,19,20,21]. LC and LM are coproduced by the Streptomyces strain, there has been no information about their sites of action, nor any evidence of functional interaction between these two antibiotic compounds
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