ABSTRACT
Trivalent organoarsenicals such as methylarsenite (MAs(III)) act as antibiotics that provide a competitive advantage for producers in microbial communities. While mechanisms of resistance to trivalent organoarsenicals have been identified and characterized, how they exert antibiotic-like properties is largely unknown. To identify targets of MAs(III), a genomic library of the highly versatile gram-negative bacterium, Shewanella putrefaciens 200, was expressed in Escherichia coli and selected for MAs(III) resistance. One clone contained the S. putrefaciens murA (SpmurA), the gene for the first committed step in peptidoglycan biosynthesis. Overexpression of SpmurA confers MAs(III) resistance in E. coli. Purified SpMurA was inhibited by MAs(III), phenylarsenite (PhAs(III)) or the phosphonate antibiotic fosfomycin, but not by inorganic arsenite (As(III)). Fosfomycin inhibits MurA by binding to a conserved catalytic cysteine residue. A SpMurA with a mutation in the cysteine became resistant to fosfomycin but remained sensitive to MAs(III), suggesting that the two compounds have different mechanisms of action. Our results demonstrate that organoarsenicals have the potential to be a new class of peptidoglycan biosynthesis inhibitors that can address the global threat of antibiotic resistance.
