Title: Arsinothricin, an arsenic-containing non-proteinogenic amino acid analog of glutamate, is a broad-spectrum antibiotic.
Authors: Nadar, Venkadesh Sarkarai; Chen, Jian; Dheeman, Dharmendra S; Galván, Adriana Emilce; Yoshinaga-Sakurai, Kunie; Kandavelu, Palani; Sankaran, Banumathi; Kuramata, Masato; Ishikawa, Satoru; Rosen, Barry P; Yoshinaga, Masafumi
Published In Commun Biol, (2019)
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.
PubMed ID: 30993215
MeSH Terms: Acetylation; Anti-Bacterial Agents/chemistry*; Anti-Bacterial Agents/isolation & purification; Anti-Bacterial Agents/pharmacology*; Arsenicals/chemistry*; Arsenicals/isolation & purification; Arsenicals/pharmacology*; Burkholderia gladioli/drug effects; Burkholderia gladioli/metabolism*; Cell Survival/drug effects; Drug Resistance, Multiple, Bacterial/drug effects; Escherichia coli/drug effects; Escherichia coli/metabolism; Genes, Bacterial/genetics; Glutamate-Ammonia Ligase/analysis; Glutamic Acid/analogs & derivatives*; Humans; Microbial Sensitivity Tests; Mycobacterium bovis/drug effects; Operon; THP-1 Cells