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.
Highlights
The emergence and spread of antimicrobial resistance highlights the urgent need for new antibiotics
In addition to M. tuberculosis, the World Health Organization recently issued a global priority pathogen list of antibiotic-resistant bacteria that pose the greatest threat to human health to guide and promote research and development of new antibiotics[4]
To determine whether AST has antibiotic activity, we examined its ability to inhibit growth of bacteria using environmental isolates
Summary
The emergence and spread of antimicrobial resistance highlights the urgent need for new antibiotics. 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. 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. The World Health Organization declares multidrug-resistant tuberculosis a global public health crisis, calling for a pressing need for development of new and innovative antibiotics[3]. In addition to M. tuberculosis, the World Health Organization recently issued a global priority pathogen list of antibiotic-resistant bacteria that pose the greatest threat to human health to guide and promote research and development of new antibiotics[4].
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