Abstract
The dramatic increase in bacterial resistance to
antibiotics is a grave threat to global health. A dearth of new antibiotics has
fostered the emergence and worldwide spread of multidrug resistant (MDR)
bacteria, resulting in an increase of serious infections with high mortality
rates. To overcome this serious health concern, discovery and development of
new antibiotics are urgently needed. Arsinothricin
[2-amino-4-(hydroxymethylarsinoyl)-butanoic acid or AST] has broad spectrum
antibiotic activity and is effective against both Gram-positive and
Gram-negative bacteria, including carbapenem-resistant Enterobacter cloacae (CRE), one of the World Health Organization critical
priority pathogens, and Mycobacterium bovis BCG, a
causative agent of animal tuberculosis that is closely related to the human
pathogen MTB. AST is produced by the rice rhizosphere
bacterium Burkholderia gladioli GSRB05. However, the amounts of AST
produced by such bacterium are insufficient for further biochemical and
clinical characterization of this antibiotic and for development of more
effective derivatives. Overcoming this obstacle requires a chemical synthetic
process.FIU inventors have developed methods for the semi-synthesis of the antibiotic AST and derivatives.
These methods comprise steps for synthesizing the precursor of AST, hydroxyarsinothricin [2-amino-4-(dihydroxyarsonoyl)butanoic
acid or AST-OH], and steps of converting
AST-OH to AST through an enzymatic methylation of AST-OH. Advantageously, it is anticipated that both the chemical synthesis and
enzymatic methylation can be scaled up to produce AST
and its derivatives in amounts sufficient for further drug development.
Benefit
Provides a simple synthesis method of AST-OH and its derivativesCan be scaled up to produce AST and its derivatives in amounts sufficient for further drug developmentEliminates the necessity of conversion of pentavalent arsenic acids with toxic SO2 gas, and challenging displacement of hydroxyl group with chloride
Market Application
Drug development: antibacterial candidates against bacterial species from both Gram-positive and Gram-negative
Publications
Semisynthesis of the Organoarsenical Antibiotic
Arsinothricin J. Nat. Prod. 2020, 83, 9, 2809–2813
Brochure
