Mechanism of action and selectivity
Fosfomycin belongs to the group of murein monomer synthesis inhibitors. Its primary target is the initial stage of bacterial cell wall peptidoglycan assembly.
Chemically, the drug is a structural analogue of phosphoenolpyruvate (PEP). Its biochemical action relies on the irreversible blockade of enzymatic condensation. The antibiotic induces covalent modification of the active site of the enzyme UDP-N-acetylglucosamine enolpyruvyltransferase (referred to as MurA). This process reliably blocks the formation of UDP-N-acetylmuramic acid (UDP-NAM) from its precursor, uridine diphosphate-N-acetylglucosamine (UDP-NAG). Without this step, murein monomers simply cannot form.
An important property of the drug is its selective toxicity. It has absolutely no effect on human enzymes (enolase, pyruvate kinase, or carboxykinase), making it relatively non-toxic to the host organism.
Transport and antibacterial spectrum
To act on its target, the antibiotic must enter the microbial cell. Fosfomycin achieves this via active transport, utilizing bacterial nutrient transport systems—glycerophosphate or glucose-6-phosphate transporters.
The drug exerts a bactericidal effect and has a broad spectrum of activity:
- Gram-negative bacteria (primary target): Escherichia coli (E. coli), Klebsiella species, Proteus (P. mirabilis, P. vulgaris), as well as Citrobacter, Enterobacter, Serratia, and Morganella morganii.
- Gram-positive bacteria: Staphylococci, streptococci, and enterococci. However, efficacy against them is lower due to the absence of selective transporters required for drug entry in certain Gram-positive microorganisms.
Pharmacokinetics and Clinical Application
The primary pharmacokinetic feature of fosfomycin is its excretion. It is excreted in the urine in an entirely unchanged form, achieving extremely high concentrations in the urinary tract.
This provides a massive clinical advantage: for uncomplicated urinary tract infections (cystitis, urethritis) caused by susceptible flora, a single oral dose (3 g) is sufficient. This single dose is equivalent to a course of multiple doses of other antibiotics.
In addition to UTI therapy, the drug is used for:
- Prevention and treatment of infectious complications during surgical interventions and transurethral diagnostics.
- Treatment of pregnant women (acting as a safe alternative to fluoroquinolones, which are contraindicated during this period).
Dosing regimens depend on the route of administration. For oral use, the drug is prescribed once daily. For parenteral use: intravenously every 6–8 hours, or intramuscularly twice daily.
Adverse effects and related compounds
The drug is well tolerated. Adverse effects are rare (in 1–10% of patients) and are typically limited to headache, nausea, or diarrhea.
When administered orally, it is important to consider drug interactions that may decrease absorption of the antibiotic. These include:
- Antacids.
- Calcium salts.
- Drugs that increase gastrointestinal peristalsis (e.g., metoclopramide).
The group of murein monomer synthesis inhibitors also includes a related compound — fosmidomycin. It is also a PEP analogue and has a similar mechanism of action. However, in clinical practice, the development of resistance has been noted with it. Resistance mechanisms include mutations in transport systems (glycerophosphate or glucose-6-phosphate transporters) and active elimination of the drug from the cell (efflux) via specific pump proteins, as described in E. coli strains. Fosmidomycin is not used in the Russian Federation.
Briefly: answers to topical questions
What specific mechanisms of bacterial resistance are described specifically for fosfomycin?
The following specific mechanisms of bacterial resistance have been described for fosfomycin group drugs:
- Mutations in transport systems — alterations in glycerophosphate or glucose-6-phosphate transporters, which disrupt the active transport of the antibiotic into the microbial cell.
- Active elimination (efflux) — removal of the drug from the cell via specific pump proteins (this mechanism has been described in Escherichia coli strains).
With which antibiotic groups does fosfomycin exhibit synergy in combination therapy?
Sources describe potential synergy of fosfomycin with daptomycin: the combination may increase daptomycin binding to bacterial cell membranes by reducing the positive surface charge of the bacterial wall. Fosfomycin is also included in alternative combinations with imipenem/cilastatin and linezolid, although synergy for these combinations is not explicitly stated in the sources.
It is easy to remember the target of fosfomycin: it blocks the MurA enzyme, which converts UDP-NAG into UDP-NAM. Fosfomycin is a structural analogue of PEP (phosphoenolpyruvate), so it tricks the bacterium right at the start of cell wall construction.
Class and exam questions
Why is fosfomycin safe for humans if it blocks enzymes?
The drug exhibits high selective toxicity. It does not affect host enzymes (enolase, pyruvate kinase, carboxykinase), making it relatively non-toxic to humans.
How does the antibiotic penetrate inside the bacterium?
Via active transport. Fosfomycin utilizes bacterial nutrient transport systems — specific glycerophosphate or glucose-6-phosphate transporters.
Why is a single dose of the drug sufficient for cystitis?
Fosfomycin is excreted unchanged in the urine, achieving extremely high concentrations there. A single oral dose of 3 g is equivalent to a multi-day course of other antibiotics in the treatment of urinary tract infections.
What else to study on this topic
- Biochemical basis of murein monomer formation and the role of UDP-N-acetylmuramic acid.
- Structural and functional features of the enzyme N-acetylglucosamine-3-O-enolpyruvyltransferase (MurA).
- Mechanisms of bacterial resistance: transport system mutations and efflux pump proteins.
- Comparative characteristics of fosfomycin and fluoroquinolones in the treatment of urinary tract infections in pregnant women.
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