Studies on the biodegradation of fosfomycin: Growth of Rhizobium huakuii PMY1 on possible intermediates synthesised chemically

Abstract

The first step of the mineralisation of fosfomycin by R. huakuii PMY1 is hydrolytic ring opening with the formation of (1R,2R)-1,2-dihydroxypropylphosphonic acid. This phosphonic acid and its three stereoisomers were synthesised by chemical means and tested as their ammonium salts for mineralisation as evidenced by release of P(i). Only the (1R,2R)-isomer was degraded. A number of salts of phosphonic acids such as (+/-)-1,2-epoxybutyl-, (+/-)-1,2-dihydroxyethyl-, 2-oxopropyl-, (S)-2-hydroxypropyl-, (+/-)-1-hydroxypropyl- and (+/-)-1-hydroxy-2-oxopropylphosphonic acid were synthesised chemically, but none supported growth. In vitro C-P bond cleavage activity was however detected with the last phosphonic acid. A mechanism involving phosphite had to be discarded as it could not be used as a phosphorus source. R. huakuii PMY1 grew well on (R)- and (S)-lactic acid and hydroxyacetone, but less well on propionic acid and not on acetone or (R)- and (+/-)-1,2-propanediol. The P(i) released from (1R,2R)-1,2-dihydroxypropylphosphonic acid labelled with one oxygen-18 in the PO3H2 group did not stay long enough in the cells to allow complete exchange of 18O for 16O by enzymic turnover.

Kinetics and Mechanism of Cerium(IV) Oxidation of Fosfomycin Disodium Salt: An Antibiotic Drug in Acid Perchlorate Solutions

“…Only some reports on the biodegradation of fosfomycin has been reported. [4] Hence, in the present study, we have investigated the oxidation of fosfomycin by cerium (IV) in aqueous perchloric acid medium and based on the experimental results a suitable mechanism is proposed.…”

“…Its simple structure consists of the active bactericidal epoxy group and a directly bonded carbon atom to the centrally positioned phosphorous (see Figure 1) with an oxirane ring that is fairly labile under acidic and basic conditions. [2][3][4] A nucleophile can attack fosfomycin regioselectively on either of the two carbon atoms and the P-C bond is highly stable under a variety of conditions, even under forcing acidic and basic conditions. Fosfomycin is a white, very hygroscopic powder, very soluble in water.…”

Studies on the Biodegradation of Fosfomycin: Synthesis of 13C‐Labeled Intermediates, Feeding Experiments with Rhizobium huakuii PMY1, and Isolation of Labeled Amino Acids from Cell Mass by HPLC

“…(AE)-9: 18.4 (erroneously reported [10] to be a doublet at 17.7), 18.3 (3 C), 18.2 (3 C), 16 11 (0.368 g, 1.73 mmol), allylTMS (0.985 g, 1.38 mL, 8.65 mmol, 5 equiv), and bromotrimethylsilane (3.337 g, 2.88 mL, 21.8 mmol) in dry 1,2-C 2 H 4 Cl 2 (8.0 mL) was kept under argon for 16 h at room temperature. Volatile components were then removed in vacuo (0.50 mbar, ambient to 40 8C) and the residue was dissolved in a 1:1 mixture of EtOH/H 2 O (10 mL).…”

Chemical Biology: What is Its Role in Drug Discovery?

“…The synthesis of key intermediates in several biosynthetic pathways has also been reported and the intermediates used to understand further these pathways. For example, studies on the biosynthesis of Fosfomycin, were carried out by supplementing the growth media with chemically synthesised hypothesised intermediates (McGrath et al, 2009). The synthesis of UDP-Glc-2,3-diNAcA, a key intermediate in the biosynthesis of cell surface polysaccharides, was accomplished and the compound used to study this process (Rejzek et al, 2009).…”