ABSTRACT
There is an urgent need for new antibiotics to combat the emergence and spread of antibiotic resistance. Bacteria evolved the ability to utilize the pervasive environmental toxic metalloid arsenic to produce the potent broad-spectrum antibiotic, arsinothricin (AST). AST is a non-proteinogenic analog of glutamate that inhibits glutamine synthetase. It is an effective broad-spectrum antibiotic against both Gram-positive and Gram-negative bacteria including major resistant pathogens, demonstrating the potential to address the global threat of drug resistance. New chemical synthesis methods have been devised for AST that are necessary for long process of drug tests and development. AST is biosynthesized via two steps involving sequential formation of two C-As bonds catalyzed by ArsL, the novel radicalS-adenosylmethionine (SAM) protein, and ArsM, As(III) SAM methyltransferase. The arsN1 gene confers resistance to AST by acetylation of the α-amino group. Crystal structures of ArsN1 N-acetyltransferase, with or without AST, shed light on the mechanism of its substrate selectivity. Using this information inhibitors of AST have been identified. One inhibitor, 3-phosphonoalanine, reverses AST resistance. These findings have the potential for development of a new class of organoarsenical antimicrobials and ArsN1 inhibitors.
