A Potent Seryl tRNA Synthetase Inhibitor SB-217452 Isolated from a Streptomyces species.

Abstract

A potent inhibitor of seryl tRNAsynthetase, designated SB-217452 has been isolated from Streptomyces sp. ATCC 700974. The fermentation, isolation, structure elucidation and some properties are described. SB-217452 showed inhibitory activity against both Staphylococcus aureus and rat seryl tRNA synthetases, with similar IC50 values of approximately 8 nM. The inhibitor is the serine linked nucleoside moiety of the antibiotic albomycin 82. In contrast to albomycin 52, SB-217452 showed only very weak antibacterial activity against a limited range of microorganisms. The compoundhas not been previously reported as a naturally occurring metabolite. In addition to SB-217452, albomycin S2 Fe3+ complex and the novel Al3+ complex were isolated from the fermentation. These complexes had no seryl tRNAsynthetase inhibitory activity. Aminoacyl-tRNA synthetases catalyze one of the most critical steps in protein biosynthesis. They attach one of twenty amino acids to one of about sixty tRNAs. Their specificities with regard to amino acids and tRNAs are responsible for the accurate primary structures of proteins. The enzymes are essential for cell viability, and are

Siderophore-Based Iron Acquisition and Pathogen Control

“…Because of its similarity to fungal ferrichromes, albomycin is recognized by the FhuA receptor and the FhuD binding protein, which was shown by both mutagenesis (259) and crystallization studies (58). After hydrolysis from the siderophore carrier, the serylthioribosyl pyrimidine moiety blocks protein biosynthesis by inhibiting seryl-tRNA synthetases (307). Danomycins and salmycins produced by actinomycetes contain the trishydroxamate danoxamine as a siderophore unit that is connected with an aminoglycoside moiety (147,326) (13,316).…”

Structure and function of a serine carboxypeptidase adapted for degradation of the protein synthesis antibiotic microcin C7

“…Nature has overcome both of these limitations by employing a Trojan horse strategy, in which the drug molecule is conjugated with a specialized module that facilitates active transport into bacterial cells where antibiotic activity is exerted after intracellular processing. Examples of naturally occurring antibiotics that employ this Trojan horse strategy include the LeuRS inhibitor agrocin 84 (in which the toxic group is linked through a phosphoramidate bond to a D-glucofuranosyloxyphosphoryl moiety) (5), the SerRS inhibitor albomycin (a toxic group covalently linked to a hydroxymate siderophore) (6), and the AspRS inhibitor microcin C7 (Fig. 1A, 1) (McC7; consisting of a modified aspartyl-adenylate linked to a six-residue peptide carrier).…”

Albomycin Uptake via a Ferric Hydroxamate Transport System ofStreptococcus pneumoniaeR6

“…strain ATCC 700974 and shown to inhibit in vitro seryl-tRNA synthetases (37). SB-217452 is highly active against isolated tRNA synthetases (50% inhibitory concentration value of 8 nM) but poorly active against bacteria, e.g., MIC of 256 g/ml (0.4 mM) for Staphylococcus aureus, presumably because of its low permeation into the bacterial cells (37).…”