Mechanism of Action of Fosfomycin
Fosfomycin irreversibly inhibits UDP-N-acetylglucosamine enolpyruvyl transferase (MurA), the enzyme that catalyzes the first committed step in bacterial peptidoglycan (cell wall) biosynthesis. 1, 2
Molecular Mechanism
Fosfomycin is a phosphonic acid derivative that acts as a structural analog of phosphoenolpyruvate (PEP), the natural substrate of MurA 2, 3. The antibiotic enters bacterial cells through specific membrane transporters (GlpT and UhpT in gram-negative bacteria), then binds competitively to the active site of MurA 1, 3. Once bound, fosfomycin undergoes nucleophilic attack by an active-site cysteine residue, resulting in covalent modification and irreversible enzyme inactivation 2, 3.
This mechanism blocks the condensation of uridine diphosphate-N-acetylglucosamine (UDP-GlcNAc) with PEP, preventing the formation of UDP-N-acetylmuramic acid, an essential precursor for peptidoglycan synthesis 1, 3. Without functional peptidoglycan, bacterial cell wall integrity is compromised, leading to bactericidal activity 1, 4.
Unique Characteristics
Fosfomycin's mechanism is distinct from all other antibiotics, occurring at an earlier step in cell wall synthesis than β-lactams, which explains the general absence of cross-resistance between fosfomycin and other antibiotic classes including β-lactams and aminoglycosides. 1, 2
The antibiotic also reduces bacterial adherence to uroepithelial cells, contributing to its efficacy in urinary tract infections 1. MurA and the related enzyme EPSP synthase (target of the herbicide glyphosate) are the only known enzymes that catalyze enolpyruvyl transfer from PEP, making this a highly specific and exploitable target 2.
Resistance Mechanisms
Bacterial resistance to fosfomycin develops through three primary pathways, listed in order of decreasing clinical frequency 5, 3:
- Modification of membrane transporters (GlpT, UhpT) that prevent fosfomycin entry into the bacterial cell—this is the most common resistance mechanism 5, 3
- Acquisition of plasmid-encoded fosfomycin-modifying enzymes (FosA, FosB, FosC, FosX) that inactivate the antibiotic before it reaches its target 5, 3
- MurA target mutations that prevent fosfomycin binding while maintaining enzyme function 5, 3
- Inactivation of glycolytic enzymes in the Embden-Meyerhof-Parnas pathway, a novel mechanism described in Stenotrophomonas maltophilia 6
Resistance develops more readily in vitro than in vivo, with mutation frequency highest in Pseudomonas aeruginosa and Klebsiella species compared to E. coli 5. FosA-like genes are increasingly prevalent in carbapenem-resistant K. pneumoniae, with susceptibility rates ranging from 39% to 99% depending on geographic location 7.