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Synthesis and Antimicrobial Evaluation of γ‑Borono Phosphonate Compounds in Escherichia coli and Mycobacterium smegmatis
journal contribution
posted on 2019-08-23, 08:29 authored by Giulia Mancini, Maria Bouda, James M. Gamrat, John W. TomshoDrug
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 Escherichia coli wild type, E. coli Δglycerol-3-phosphate transporter,
and Mycobacterium smegmatis. Despite
its structural similarities, the γ-borono phosphonate compound
shows antimicrobial activity against E. coli 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 E. coli 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.
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MEPenzyme 1- deoxylulose -5-phosphate reductoisomeraseisopentenyl pyrophosphate chemical rescueγ- borono phosphonate compoundcoli Δ glycerol -3-phosphate transporterEscherichia coliinhibitionantimicrobial activityfosmidomycinMycobacterium smegmatis Drug resistanceDXRγ- borono phosphonate compoundspathwayγ- borono phosphonate analog
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