Florida International University

Masafumi Yoshinaga

Barry P Rosen

Stanislaw F Wnuk

Md Abu Hasan Howlader

Sk Md Sazzad Hossain Suzol

Jun Li

Guodong Niu

Certain embodiments of the invention pertain to a method of treating an infection in a subject caused by an infectious agent other than, the method comprising administering to the subject arsinothricin or a salt thereof. The infectious agent other thancan be a bacterium, protozoan, helminth, archaebacterium, or a fungus. In preferred embodiments, the infectious agent is, or. The invention also pertains to a method of treating an infection in a subject caused by an infectious agent, comprising administering to the subject arsinothricin or a salt thereof in combination with an inhibitor of phosphinothricin N-acetyltransferase or arsinothricin N-acetyltransferase. In certain such embodiments, the infectious agent expresses phosphinothricin N-acetyltransferase or arsinothricin N-acetyltransferase. Further embodiments provide compositions comprising arsinothricin or a salt thereof and an inhibitor of phosphinothricin N-acetyltransferase or arsinothricin N-acetyltransferase.

Arsinothricin and methods of treating infections using arsinothricin

The subject invention provides arsinothricin (AST) or salts thereof, and compositions comprising AST or a salt thereof for use as multi-stage antimalarials. The subject invention also provides methods for treating, inhibiting and/or preventing malaria infection and transmission by using AST or salts thereof, or compositions comprising AST or a salt thereof. Advantageously, AST or a salt thereof inhibits glutamine synthetase (GS) of malaria pathogens without exhibiting cytotoxicity to human host.

Arsinothricin as a multi-stage antimalarial

The subject invention provides methods for the chemical synthesis of racemic arsinothricin (D,L-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 the resulting sodium salt of trivalent arsenic intermediate with methyl iodide. The enzyme AST N-acetyltransferase (ArsN1) was utilized to purify L-AST from racemic AST. This expedient chemical synthesis of AST provides a source of this novel antibiotic for future drug development.

Chemical synthesis of the organoarsenical antibiotic arsinothricin

The subject invention provides methods for the chemical synthesis of racemic arsinothricin (D,L-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 the resulting sodium salt of trivalent arsenic intermediate with methyl iodide. The enzyme AST N-acetyltransferase (ArsNl) was utilized to purify L-AST from racemic AST. This expedient chemical synthesis of AST provides a source of this novel antibiotic for future drug development.

The subject invention provides methods and procedures for synthesis and/or semi-synthesis of the novel antibiotic arsinothricin (AST) and derivatives. Arsinothricin (AST), a new broad-spectrum organoarsenical antibiotic, is a non-proteinogenic analog of glutamate that effectively inhibits glutamine synthetase. The subject invention provides chemical synthesis of an intermediate in the pathway of AST synthesis, hydroxyarsinothricin (AST-OH), which can be converted to AST by enzymatic methylation catalyzed by the ArsM As(III) S-adenosylmethionine methyltransferase. The methods provide a source of the novel antibiotic that will be required for future clinical trials. The subject invention also provides AST derivatives as a new class of antibiotics.

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Doral, FL, United States of America

Masafumi Yoshinaga