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  1. Arsenicals are one of the oldest treatments for a variety of human disorders. Although infamous for its toxicity, arsenic is paradoxically a therapeutic agent that has been used since ancient times for the treatment of multiple diseases. The use of most arsenic-based drugs was abandoned with the discovery of antibiotics in the 1940s, but a few remained in use such as those for the treatment of trypanosomiasis. In the 1970s, arsenic trioxide, the active ingredient in a traditional Chinese medicine, was shown to produce dramatic remission of acute promyelocytic leukemia similar to the effect of all-trans retinoic acid. Since then, there has been a renewed interest in the clinical use of arsenicals. Here the ancient and modern medicinal uses of inorganic and organic arsenicals are reviewed. Included are antimicrobial, antiviral, antiparasitic and anticancer applications. In the face of increasing antibiotic resistance and the emergence of deadly pathogens such as the severe acute respiratory syndrome coronavirus 2, we propose revisiting arsenicals with proven efficacy to combat emerging pathogens. Current advances in science and technology can be employed to design newer arsenical drugs with high therapeutic index. These novel arsenicals can be used in combination with existing drugs or serve as valuablemore »alternatives in the fight against cancer and emerging pathogens. The discovery of the pentavalent arsenic-containing antibiotic arsinothricin, which is effective against multidrug-resistant pathogens, illustrates the future potential of this new class of organoarsenical antibiotics.« less
  2. Abstract

    The pentavalent organoarsenical arsinothricin (AST) is a natural product synthesized by the rhizosphere bacteriumBurkholderia gladioliGSRB05.AST is a broad‐spectrum antibiotic effective against human pathogens such as carbapenem‐resistantEnterobacter cloacae.It is a non‐proteogenic amino acid and glutamate mimetic that inhibits bacterial glutamine synthetase. The AST biosynthetic pathway is composed of a three‐gene cluster,arsQML.ArsL catalyzes synthesis of reduced trivalent hydroxyarsinothricin (R‐AST‐OH), which is methylated by ArsM to the reduced trivalent form of AST (R‐AST). In the culture medium ofB. gladioli, both trivalent species appear as the corresponding pentavalent arsenicals, likely due to oxidation in air. ArsQ is an efflux permease that is proposed to transport AST or related species out of the cells, but the chemical nature of the actual transport substrate is unclear. In this study,B. gladioli arsQwas expressed inEscherichia coliand shown to confer resistance to AST and its derivatives. Cells ofE. coliaccumulate R‐AST, and exponentially growing cells expressingarsQtake up less R‐AST. The cells exhibit little transport of their pentavalent forms. Transport was independent of cellular energy and appears to be equilibrative. A homology model of ArsQ suggests that Ser320 is in the substrate binding site. A S320A mutant exhibits reduced R‐AST‐OH transport, suggesting that it plays a role in ArsQ function.more »The ArsQ permease is proposed to be an energy‐independent uniporter responsible for downhill transport of the trivalent form of AST out of cells, which is oxidized extracellularly to the active form of the antibiotic.

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    Free, publicly-accessible full text available February 13, 2024
  3. Over 300 species of naturally occurring-organoarsenicals have been identified with the development of modern analytical techniques. Why there so many environmental organoarsenicals exist is a real enigma. Are they protective or harmful? Or are they simply by-products of existing pathways for non-arsenical compounds? Fundamental unanswered questions exist about their occurrence, prevalence and fate in the environment, metabolisms, toxicology and biological functions. This review focuses on possible answers. As a beginning, we classified them into two categories: water-soluble and lipid-soluble organoarsenicals (arsenolipids). Continual improvements in analytical techniques will lead to identification of additional organoarsenicals. In this review, we enumerate identified environmental organoarsenicals and speculate about their pathways of synthesis and degradation based on structural data and previous studies. Organoarsenicals are frequently considered to be nontoxic, yet trivalent methylarsenicals, synthetic aromatic arsenicals and some pentavalent arsenic-containing compounds have been shown to be highly toxic. The biological functions of some organoarsenicals have been defined. For example, arsenobetaine acts as an osmolyte, and membrane arsenolipids have a phosphate-sparing role under phosphate-limited conditions. However, the toxicological properties and biological functions of most organoarsenicals are largely unknown. The objective of this review is to summarize the toxicological and physiological properties and to provide novel insights intomore »future studies.« less
  4. Tang, Xiaoyu (Ed.)
    ABSTRACT The soil bacterium Burkholderia gladioli GSRB05 produces the natural compound arsinothricin [2-amino-4-(hydroxymethylarsinoyl) butanoate] (AST), which has been demonstrated to be a broad-spectrum antibiotic. To identify the genes responsible for AST biosynthesis, a draft genome sequence of B. gladioli GSRB05 was constructed. Three genes, arsQML , in an arsenic resistance operon were found to be a biosynthetic gene cluster responsible for synthesis of AST and its precursor, hydroxyarsinothricin [2-amino-4-(dihydroxyarsinoyl) butanoate] (AST-OH). The arsL gene product is a noncanonical radical S -adenosylmethionine (SAM) enzyme that is predicted to transfer the 3-amino-3-carboxypropyl (ACP) group from SAM to the arsenic atom in inorganic arsenite, forming AST-OH, which is methylated by the arsM gene product, a SAM methyltransferase, to produce AST. Finally, the arsQ gene product is an efflux permease that extrudes AST from the cells, a common final step in antibiotic-producing bacteria. Elucidation of the biosynthetic gene cluster for this novel arsenic-containing antibiotic adds an important new tool for continuation of the antibiotic era. IMPORTANCE 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 ourmore »antibiotic era. Here, we report identification of the biosynthetic gene cluster for arsinothricin and demonstrate that only three genes, two of which are novel, are required for the biosynthesis and transport of arsinothricin, in contrast to the phosphonate counterpart, phosphinothricin, which requires over 20 genes. Our discoveries will provide insight for the development of more effective organoarsenical antibiotics and illustrate the previously unknown complexity of the arsenic biogeochemical cycle, as well as bring new perspective to environmental arsenic biochemistry.« less
  5. We report two routes of chemical synthesis of arsinothricin (AST), the novel organoarsenical antibiotic. One is by condensation of the 2-chloroethyl(methyl)arsinic acid with acetamidomalonate, and the second involves reduction of the N -acetyl protected derivative of hydroxyarsinothricin (AST-OH) and subsequent methylation of a trivalent arsenic intermediate with methyl iodide. The enzyme AST N -acetyltransferase (ArsN1) was utilized to purify l -AST from racemic AST. This chemical synthesis provides a source of this novel antibiotic for future drug development.
  6. null (Ed.)
    The oxidation of highly toxic arsenite (As(III)) was studied using humic acid-coated magnetite nanoparticles (HA-MNP) as a photosensitizer. Detailed characterization of the HA-MNP was carried out before and after the photoinduced treatment of As(III) species. Upon irradiation of HA-MNP with 350 nm light, a portion of the As(III) species was oxidized to arsenate (As(V)) and was nearly quantitatively removed from the aqueous solution. The separation of As(III) from the aqueous solution is primarily driven by the strong adsorption of As(III) onto the HA-MNP. As(III) removals of 40–90% were achieved within 60 min depending on the amount of HA-MNP. The generation of reactive oxygen species (•OH and 1O2) and the triplet excited state of HA-MNP (3HA-MNP*) was monitored and quantified during HA-MNP photolysis. The results indicate 3HA-MNP* and/or singlet oxygen (1O2) depending on the reaction conditions are responsible for converting As(III) to less toxic As(V). The formation of 3HA-MNP* was quantified using the electron transfer probe 2,4,6-trimethylphenol (TMP). The formation rate of 3HA-MNP* was 8.0 ± 0.6 × 10−9 M s−1 at the TMP concentration of 50 µM and HA-MNP concentration of 1.0 g L−1. The easy preparation, capacity for triplet excited state and singlet oxygen production, and magnetic separation suggestmore »HA-MNP has potential to be a photosensitizer for the remediation of arsenic (As) and other pollutants susceptible to advanced oxidation.« less