Arsinothricin, an arsenic-containing non-proteinogenic amino acid analog of glutamate, is a broad-spectrum antibiotic

Venkadesh Sarkarai Nadar, Jian Chen, Dharmendra S Dheeman, Adriana Emilce Galván, Kunie Yoshinaga-Sakurai, Palani Kandavelu, Banumathi Sankaran, Masato Kuramata, Satoru Ishikawa, Barry P Rosen, Masafumi Yoshinaga

Research output: Contribution to journalArticlepeer-review

Abstract

The emergence and spread of antimicrobial resistance highlights the urgent need for new antibiotics. Organoarsenicals have been used as antimicrobials since Paul Ehrlich's salvarsan. Recently a soil bacterium was shown to produce the organoarsenical arsinothricin. We demonstrate that arsinothricin, a non-proteinogenic analog of glutamate that inhibits glutamine synthetase, is an effective broad-spectrum antibiotic against both Gram-positive and Gram-negative bacteria, suggesting that bacteria have evolved the ability to utilize the pervasive environmental toxic metalloid arsenic to produce a potent antimicrobial. With every new antibiotic, resistance inevitably arises. The arsN1 gene, widely distributed in bacterial arsenic resistance (ars) operons, selectively confers resistance to arsinothricin by acetylation of the α-amino group. Crystal structures of ArsN1 N-acetyltransferase, with or without arsinothricin, shed light on the mechanism of its substrate selectivity. These findings have the potential for development of a new class of organoarsenical antimicrobials and ArsN1 inhibitors.

Original languageEnglish
Pages (from-to)131
JournalCommunications Biology
Volume2
DOIs
Publication statusPublished - 15 Apr 2019

Keywords

  • Acetylation
  • Anti-Bacterial Agents/chemistry
  • Arsenicals/chemistry
  • Burkholderia gladioli/drug effects
  • Cell Survival/drug effects
  • Drug Resistance, Multiple, Bacterial/drug effects
  • Escherichia coli/drug effects
  • Genes, Bacterial/genetics
  • Glutamate-Ammonia Ligase/analysis
  • Glutamic Acid/analogs & derivatives
  • Humans
  • Microbial Sensitivity Tests
  • Mycobacterium bovis/drug effects
  • Operon
  • THP-1 Cells

Research Beacons, Institutes and Platforms

  • Manchester Institute of Biotechnology

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