Towards the biodegradation pathway of fosfomycin

Abstract

Three functionalised propylphosphonic acids were synthesised to study C-P bond cleavage in R. huakuii PMY1. (R)-1-Hydroxy-2-oxopropylphosphonic acid [(R)-5] was prepared by chiral resolution of (±)-dimethyl 1-hydroxy-2-methylallyllphosphonate [(±)-12], followed by ozonolysis and deprotection. The N-(l-alanyl)-substituted (1R,2R)-2-amino-1-hydroxypropylphosphonic acid 10, a potential precursor for 2-oxopropylphosphonic acid (5) in cells, was obtained by coupling the aminophosphonic acid with benzotriazole-activated Z-l-alanine and hydrogenolytic deprotection. (1R*,2R*)-1,2-Dihydroxy-3,3,3-trifluoropropylphosphonic acid, a potential inhibitor of C-P bond cleavage after conversion into its 2-oxo derivative in the cell, was accessed from trifluoroacetaldehyde hydrate via hydroxypropanenitrile 21, which was silylated and reduced to the aldehyde (±)-23. Diastereoselective addition of diethyl trimethylsilyl phosphite furnished diastereomeric α-siloxyphosphonates. The less polar one was converted to the desired racemic phosphonic acid (±)-(1R*,2R*)-9 as its ammonium salt.

Asymmetric Transfer Hydrogenation as a Key Step in the Synthesis of the Phosphonic Acid Analogs of Aminocarboxylic Acids

“…The obtained α‐oxo‐phosphonates can be directly used after extractive removal of the remaining oxidant. Noteworthy, we did not aim for the preparation of a suitable α‐oxo‐phosphonate for the synthesis of phospha‐threonine, as it cannot be accessed in the desired configuration by the outlined method and is available in a simple one‐step procedure from commercially available Fosfomycin [47] …”

“…Noteworthy, we did not aim for the preparation of a suitable α-oxo-phosphonate for the synthesis of phospha-threonine, as it cannot be accessed in the desired configuration by the outlined method and is available in a simple one-step procedure from commercially available Fosfomycin. [47] The preparation of suitable α-oxo-phosphonates for the synthesis of all other phospha-analogs to the proteinogenic αaminocarboxylic acids was attempted. However, we did not succeed to prepare a suitable precursor for the synthesis of phosphahistidine by the outlined procedures (A or B).…”

Synthetic Phosphonic Acids as Potent Tools to Study Phosphonate Enzymology

“…To prove this hypothesis, we synthesized both enantiomers of 25 to evaluate them separately with cultures of these microbes. 46 While the racemate of 25 did not show any detectable phosphate release in living cells, there was detectable in vitro P-C bond-cleavage activity. To explain this fact, inhibition of the responsible enzyme by the nonnatural enantiomer in vivo has been proposed by Quinn et al as one possible explanation, which makes separate evaluation of both enantiomers necessary.…”

The Impact of the Antibiotic Fosfomycin on Wastewater Communities Measured by Flow Cytometry

“…Flow cytometry was used as a tool to follow dynamic changes of arising and disappearing subcommunities to reveal diverging and segregated responses of cell subsets of a WWC to fosfomycin. In parallel, a bio-augmented ( gfp -labeled) Pseudomonas putida strain as a typical member of WWTPs ( Chu et al, 2018 ) with inherent resistance to fosfomycin ( Falagas et al, 2019 ), and as a possible future chassis for fosfomycin biodegradation pathways ( Pallitsch et al, 2017 ; Nikel and de Lorenzo, 2018 ), was used as a model and marker organism, and its fate was continually tracked in a WWC under fosfomycin pressure. Exemplary WWCs and dominant cytometrically sorted subcommunities were analyzed taxonomically based on the 16S rRNA gene to identify phenotypes that may have been particularly selected by fosfomycin.…”