Synthesis and Antimicrobial Evaluation of γ-Borono Phosphonate Compounds in and .

Drug resistance in bacteria is a serious threat, and drugs with novel modes of action are constantly needed. Fosmidomycin is a naturally occurring antibiotic that inhibits the nonmevalonate pathway via inhibition of the enzyme 1-deoxylulose-5-phosphate reductoisomerase (DXR). This work is the first report in which a boronic acid is evaluated as an isostere of the retrohydroxamate moiety of fosmidomycin. We report the novel synthesis of a γ-borono phosphonate analog of fosmidomycin and its corresponding prodrugs. We evaluate the inhibition of DXR and the antimicrobial activity of γ-borono phosphonate compounds against wild type, Δglycerol-3-phosphate transporter, and . Despite its structural similarities, the γ-borono phosphonate compound shows antimicrobial activity against with a mechanism of action that is different from fosmidomycin. This was proven with an underutilized method for studying in vitro inhibition of the MEP pathway in via isopentenyl pyrophosphate chemical rescue. These results indicate that these compounds may serve as a promising scaffold for developing a new class of antimicrobial agents.