Crystal structure of the synergistic antibiotic pair, lankamycin and lankacidin, in complex with the large ribosomal subunit

Abstract

The structures of the large ribosomal subunit of Deinococcus radiodurans (D50S) in complex with the antibiotic lankamycin (3.2 Å) and a double antibiotic complex of lankamycin and lankacidin C (3.45 Å) have been determined, in continuation of previous crystallographic studies on lankacidin-D50S complex. These two drugs have been previously reported to inhibit ribosomal function with mild synergistic effect. Lankamycin, a member of the macrolide family, binds in a similar manner to erythromycin. However, when in complex with lankacidin, lankamycin is located so that it can form interactions with lankacidin in the adjacent ribosomal binding site. When compared to the well-documented synergistic antibiotics, Streptogramins A and B, the pair of lankacidin and lankamycin bind in similar sites, the peptidyl transferase center and nascent peptide exit tunnel, respectively. Herein, we discuss the structural basis for antibiotic synergism and highlight the key factors involved in ribosomal inhibition.protein exit tunnel | ribosomes

Structural insights into species-specific features of the ribosome from the pathogen Staphylococcus aureus

“…The SA50Stel structure shows that telithromycin is bound at the MLS B K-binding site and forms the typical ketolide (and macrolide) hydrogen bond between its desosamine sugar and A2058. At this position, it is partially blocking the protein exit tunnel, as has been found in other ribosome-MLS B K complex structures (5,27,50). In the SA50Stel complex, the flexible nucleotide A2062 is rotated compared with its conformation in native SA50S, and its conformational range is minimized by the hydrogen bond with A2503 (Fig.…”

Sorting Out Antibiotics' Mechanisms of Action: a Double Fluorescent Protein Reporter for High-Throughput Screening of Ribosome and DNA Biosynthesis Inhibitors

“…Both induce Katushka2S expression, but the levels of induction are different. The binding sites of these two antibiotics are different: griseoviridin blocks A and P sites, while etamycin A binds adjacent to the peptidyl transferase center (PTC) at the peptide tunnel exit close to the macrolide's binding site (32). Effective induction of Katushka2S reporter by etamycin A is expected, due to the similarity with macrolides in both binding site and mode of action.…”

Isolation and Biosynthesis of an Azoxyalkene Compound Produced by a Multiple Gene Disruptant of Streptomyces rochei

“…Streptomyces rochei 7434AN4 produces two structurally unrelated polyketide antibiotics, lankacidin C ( 1 ) and lankamycin ( 2 ; Scheme ), and carries three linear plasmids pSLA2‐L, ‐M, and ‐S . The two antibiotics attract great attention because they inhibit peptide synthesis synergistically by binding to neighboring sites on the large ribosomal subunit . Nucleotide sequencing of the largest plasmid (pSLA2‐L, 210 614 bp) together with extensive mutational analysis revealed that the biosynthetic gene clusters for lankacidin ( lkc ) and lankamycin ( lkm ) are located on pSLA2‐L .…”

“…[4,5] Streptomycesr ochei 7434AN4 produces two structurally unrelated polyketide antibiotics, lankacidin C( 1)a nd lankamycin (2;S cheme 1), and carries three linear plasmids pSLA2-L, -M, and -S. [6] The two antibiotics attractg reat attention because they inhibit peptides ynthesis synergistically by bindingt o neighboring sites on the large ribosomal subunit. [7,8] Nucleotide sequencing of the largestp lasmid( pSLA2-L, 210 614 bp) together with extensive mutational analysisr evealed that the biosynthetic gene clusters for lankacidin( lkc)a nd lankamycin (lkm)a re located on pSLA2-L. [9] This plasmid contains two additional biosynthetic clusters, for ac ryptic type-II polyketide (roc) and ac arotenoid (crt). It also carriesm any regulatory genes, including ab iosynthetic gene srrX for the signaling molecules SRBs (S. rochei butenolides) and three tetR-type receptor genes (srrA, srrB,a nd srrC).…”