The intriguing biology and chemistry of fosfomycin: the only marketed phosphonate antibiotic

Abstract

Recently infectious diseases caused by the increased emergence and rapid spread of drug-resistant bacterial isolates have been one of the main threats to global public health because of a marked surge in both morbidity and mortality. The only phosphonate antibiotic in the clinic, fosfomycin, is a small broad-spectrum molecule that effectively inhibits the initial step in peptidoglycan biosynthesis by blocking the enzyme, MurA in both Gram-positive and Gram-negative bacteria. As fosfomycin has a novel mechanism of action, low toxicity, a broad spectrum of antibacterial activity, excellent pharmacodynamic/pharmacokinetic properties, and good bioavailability, it has been approved for clinical use in the treatment of urinary tract bacterial infections in many countries for several decades. Furthermore, its potential use for difficult-to-treat bacterial infections has become promising, and fosfomycin has become an ideal candidate for the effective treatment of bacterial infections caused by multidrug-resistant isolates, especially in combination with other therapeutic drugs. Here we aim to present an overview of the biology and chemistry of fosfomycin including isolation and characterization, pharmacology, biosynthesis and chemical synthesis since its discovery in order to not only help scientists reassess the role of this exciting drug in fighting antibiotic resistance but also build the stage for discovering more novel phosphonate antibiotics in the future.

Fig. 1. Chemical structure of fosfomycin (1a), fosfomycin calcium (1b), fosfomycin, disodium (1c), and fosfomycin trometamol (1d).

Fig. 2. Mechanism of action of fosfomycin. Chemical structure of fosfomycin mimics both glycerol-3-P (G3P) and glucose-6-P (G6P), which are transported by transporters GlpT and UhpT, respectively. MurA catalyzes the formation of UDP-GlcNac-3-O-enolpyruvate, a peptidoglycan precursor, from UDP-GlcNAc and PEP during the first step of peptidoglycan biosynthesis. Once fosfomycin (F) is present, it is transported inside the cell by GlpT and UhpT, blocking the UDP-GlcNac-3-O-enolpyruvate synthesis by mimicking the original substrate of MurA, PEP, avoiding cell wall synthesis and leading to cell death.

Fig. 3. Chemical structures of naturally occurring C–P small molecules as bioactive metabolites.

Fig. 4. Chemical structures of naturally occurring C–P small molecules as intermediates.

Fig. 5. Proposed pathways for fosfomycin biosynthesis in Streptomyces (left pathway) and Pseudomonas (right pathway).

Fig. 6. Proposed mechanism of the Fom3-catalyzed reaction. (A) HEP-CMP radical (41) is quenched by the transfer of methyl radical from Me-Cbl(iii) to give Cbl(ii), which is reduced to Cbl(i) in order to accept a new methyl group from SAM. (B) Transfer of methyl cation to HEP-CMP ketyl radical (47) followed by reduction and protonation of product radical (48).

Fig. 7. Reactions catalyzed by HppE with substrate analogs.

Fig. 8. Two possible reaction mechanisms for HppE with (S)-HPP. (A) A high-valent Fe^IV-oxo (ferryl) complex involved; (B) a highly reactive HO˙ radical as the only oxidant in the process of C–H activation in HppE.

Fig. 9. Total synthesis of fosfomycin. (A) and (B) Epoxidation of (Z)-1-propenylphosphonates; (C) and (D) 1,2-dihydroxylpropylphosphonate ring closure; (E–G) base-catalyzed halohydrinphosphonate ring closure.