Significance: Organoarsenicals are used as herbicides, pesticides, antimicrobial growth promoters, and chemical warfare agents. Environmental organoarsenicals are microbially degraded, but the molecular mechanisms of breakdown are unknown. We previously identified a two-step pathway of degradation involving sequential reduction and C⋅As bond cleavage. Here we report cloning of the gene and characterization of the gene product for a C⋅As lyase, ArsI, a member of the family of type I extradiol dioxygenases. ArsI is the only enzyme shown to be involved in degradation of the reduced forms of the herbicide monosodium methylarsonic acid and the antimicrobial growth promoter roxarsone. As arsI genes are widely distributed in bacteria, ArsI-catalyzed organoarsenic degradation is proposed to have an impact on the arsenic biogeocycle.

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.

Competition shapes evolution. Toxic metals and metalloids have exerted selective pressure on life since the rise of the first organisms on the Earth, which has led to the evolution and acquisition of resistance mechanisms against them, as well as mechanisms to weaponize them. Microorganisms exploit antimicrobial metals and metalloids to gain competitive advantage over other members of microbial communities. This exerts a strong selective pressure that drives evolution of resistance. This review describes, with a focus on arsenic and copper, how microorganisms exploit metals and metalloids for predation and how metal- and metalloid-dependent predation may have been a driving force for evolution of microbial resistance against metals and metalloids.

Antimicrobial resistance is an emerging global public health crisis, calling for urgent development of novel potent antibiotics. We propose that arsinothricin and related arsenic-containing compounds may be the progenitors of a new class of antibiotics to extend our antibiotic era.