Discovery of a new arsenic-containing antibiotic: a derivative of arsinothricin (AST)
Disciplines
Bacteriology | Biochemistry | Environmental Microbiology and Microbial Ecology | Integrative Biology | Molecular Biology | Organic Chemicals
Abstract (300 words maximum)
The rapid emergence and spread of antimicrobial resistance (AMR) present a critical public health challenge, highlighting the urgent need for novel antimicrobial agents. Arsenic, despite its toxicity, has a long history in medicine, from traditional Chinese remedies and Paul Ehrlich’s Salvarsan for syphilis to modern arsenic trioxide therapy for leukemia. A notable example is arsinothricin (AST), an arsenic-containing non-proteinogenic glutamate analog produced by Burkholderia gladioli. AST inhibits the growth of various pathogens while sparing human cells, further demonstrating the therapeutic potential of arsenic. Building on AST as a model, we aimed to discover additional novel arsenic-containing antibiotics. AST is biosynthesized via two steps catalyzed by two S-adenosylmethionine (SAM)-dependent enzymes ArsL and ArsM. arsL-guided genome mining revealed that various bacterial species possess arsLM-containing biosynthetic gene clusters (BGCs) with gene compositions distinct from the AST BGC. Among them, this study focuses on BGCs from Alicyclobacillus acidocaldarius and Deinococcus misasensis, both of which commonly contain two additional genes, ars1 and ars2, annotated to encode 4-carboxymuconolactone decarboxylase and biotin carboxylase, respectively. We hypothesize that Ars1 decarboxylates AST while Ars2 carboxylates its amino group, producing an arsenic mimetic of the phosphonate antibiotic fosmidomycin (FMS), provisionally termed methylarsmidomycin (MeASM). Liquid chromatography–inductively coupled plasma mass spectrometry (LC–ICP-MS) analysis showed that, when cultured with As (III), A. acidocaldarius and D. misasensis produce unknown arsenic species in addition to AST, supporting the hypothesis that MeASM is generated via AST derivatization. The unknown species will be purified for chemical characterization and antimicrobial assessment. In parallel, Escherichia coli cells expressing the MeASM structural genes, individually or in combinations, are being constructed to elucidate the MeASM biosynthetic pathway. This study connects a pressing clinical problem to genome-guided discovery, advancing our understanding of arsenic-based natural products and providing a foundation for developing novel therapeutics against AMR.
Use of AI Disclaimer
no
Academic department under which the project should be listed
CSM – Molecular and Cellular Biology
Primary Investigator (PI) Name
Masafumi Yoshinaga
Additional Faculty
Mohammad Abdul Halim, CSM - Chemistry and Biochemistry, mhalim1@kennesaw.edu
Discovery of a new arsenic-containing antibiotic: a derivative of arsinothricin (AST)
The rapid emergence and spread of antimicrobial resistance (AMR) present a critical public health challenge, highlighting the urgent need for novel antimicrobial agents. Arsenic, despite its toxicity, has a long history in medicine, from traditional Chinese remedies and Paul Ehrlich’s Salvarsan for syphilis to modern arsenic trioxide therapy for leukemia. A notable example is arsinothricin (AST), an arsenic-containing non-proteinogenic glutamate analog produced by Burkholderia gladioli. AST inhibits the growth of various pathogens while sparing human cells, further demonstrating the therapeutic potential of arsenic. Building on AST as a model, we aimed to discover additional novel arsenic-containing antibiotics. AST is biosynthesized via two steps catalyzed by two S-adenosylmethionine (SAM)-dependent enzymes ArsL and ArsM. arsL-guided genome mining revealed that various bacterial species possess arsLM-containing biosynthetic gene clusters (BGCs) with gene compositions distinct from the AST BGC. Among them, this study focuses on BGCs from Alicyclobacillus acidocaldarius and Deinococcus misasensis, both of which commonly contain two additional genes, ars1 and ars2, annotated to encode 4-carboxymuconolactone decarboxylase and biotin carboxylase, respectively. We hypothesize that Ars1 decarboxylates AST while Ars2 carboxylates its amino group, producing an arsenic mimetic of the phosphonate antibiotic fosmidomycin (FMS), provisionally termed methylarsmidomycin (MeASM). Liquid chromatography–inductively coupled plasma mass spectrometry (LC–ICP-MS) analysis showed that, when cultured with As (III), A. acidocaldarius and D. misasensis produce unknown arsenic species in addition to AST, supporting the hypothesis that MeASM is generated via AST derivatization. The unknown species will be purified for chemical characterization and antimicrobial assessment. In parallel, Escherichia coli cells expressing the MeASM structural genes, individually or in combinations, are being constructed to elucidate the MeASM biosynthetic pathway. This study connects a pressing clinical problem to genome-guided discovery, advancing our understanding of arsenic-based natural products and providing a foundation for developing novel therapeutics against AMR.