The antimicrobial natural product chuangxinmycin and Some synthetic analogues are potent and selective inhibitors of bacterial tryptophanyl tRNA synthetase

Regulation of an Auxiliary, Antibiotic-Resistant Tryptophanyl-tRNA Synthetase Gene via Ribosome-Mediated Transcriptional Attenuation

“…Presumably, strains with genetic mutations that affect tryptophanyl-tRNA charging have insufficient charged tryptophanyl-tRNA for the efficient synthesis of the trpRS1 leader peptide; the ensuing ribosomal stalling leads to antitermination. Similar observations have been made in E. coli, where it has been reported that strains harboring mutations in tryptophanyl-tRNA synthetase exhibit on May 12, 2018 by guest http://jb.asm.org/ a high degree of antitermination at the trp operon via ribosome-mediated transcriptional attenuation (6,43,44). Analysis of a trpRS1 ortholog in S. avermitilis.…”

“…Although indolmycin is not used clinically, its selective inhibition of bacterial tryptophanyltRNA synthetases and potent activity against methicillinresistant Staphylococcus aureus (MRSA) and Helicobacter pylori recently has renewed interest in its pharmacological potential (19). Chuangxinmycin, produced by Actinoplanes tsinanensis, also has demonstrable activity against multidrug-resistant pathogens (6). We previously reported that these antibiotics did not affect the transcription of trpRS2, whereas the open reading frame (ORF) of the trpRS1 transcript could be detected only in cultures that were treated with indolmycin or chuangxinmycin (39).…”

Prospects for Aminoacyl-tRNA Synthetase Inhibitors as New Antimicrobial Agents

“…4, structure 7) bears some structural resemblance to L-tryptophan and indolmycin and also specifically inhibits bacterial TrpRS (IC 50 ϭ 30 nM for E. coli TrpRS) (16). This antibiotic was initially reported to possess antibacterial activity against a number of gram-positive and gram-negative organisms and to show in vivo efficacy in murine models of infection involving Shigella dysenteriae and E. coli (16). Preliminary clinical data indicated that chuangxinmycin was effective for the treatment of septicemia and urinary and biliary infections caused by E. coli.…”

“…Preliminary clinical data indicated that chuangxinmycin was effective for the treatment of septicemia and urinary and biliary infections caused by E. coli. In spite of chuangxinmycin's early promise as a chemotherapeutic agent, this antibiotic has not yet been developed for medical use (16). We are unaware of resistance studies performed with chuangxinmycin.…”

A Novel Tryptophanyl-tRNA Synthetase Gene Confers High-Level Resistance to Indolmycin

“…All amounts of (Ϯ)-synthetic indolmycin described herein are corrected to reflect only the active enantiomer. Chuangxinmycin was generously provided as a gift from Richard L. Jarvest of GlaxoSmithKline (3).…”