Fosfomycin is an antibiotic with a broad spectrum of activity that has been in clinical use for over 50 years, but it has experienced a re-evaluation in recent times. The drug’s unique mechanism of action and low toxicity have positioned it as a therapeutic option against rising global rates of multi-drug resistant (MDR) bacteria. This renewed interest is driven by the need for effective agents against opportunistic pathogens that have developed resistance to conventional treatments. Pseudomonas aeruginosa, a Gram-negative bacterium, frequently causes severe, difficult-to-treat infections in vulnerable hospital patients. The interaction between this older drug and this adaptable bacterium is now a major focus in infectious disease research.
Pseudomonas aeruginosa: A Formidable Target
P. aeruginosa is a leading cause of nosocomial, or hospital-acquired, infections, contributing to high rates of morbidity and mortality. The bacterium possesses intrinsic resistance mechanisms that make it difficult to treat, even before it acquires additional resistance genes. Its outer membrane is less permeable to antibiotics compared to other Gram-negative bacteria, acting as a natural barrier to drug entry. Furthermore, it utilizes active efflux pumps, such as MexAB-OprM, which pump antibiotic molecules out of the cell before they reach their intracellular targets.
A major factor complicating treatment is P. aeruginosa’s ability to form biofilms, which are dense, protective communities encased in a self-produced matrix. This layer, composed of exopolysaccharides like alginate, shields the bacteria from the host immune system and antibiotic penetration. Within this sheltered environment, the bacteria exhibit reduced metabolic activity, which increases antibiotic tolerance significantly compared to free-floating cells. These characteristics combine to make P. aeruginosa a persistent cause of chronic infections, particularly in patients with cystic fibrosis, burn injuries, or those using mechanical ventilators.
Fosfomycin’s Unique Mechanism of Action
Fosfomycin is bactericidal and disrupts the earliest stage of bacterial cell wall synthesis, known as peptidoglycan biosynthesis. Unlike beta-lactam antibiotics, which inhibit later cross-linking, fosfomycin targets the initial cytoplasmic steps of this pathway. Specifically, the drug irreversibly inhibits the enzyme UDP-N-acetylglucosamine enolpyruvyl transferase (MurA). MurA catalyzes the transfer of an enolpyruvyl group from phosphoenolpyruvate (PEP) to UDP-N-acetylglucosamine, the first committed step in creating the cell wall precursor.
The antibiotic’s epoxy-phosphonate structure mimics the natural substrate PEP, allowing it to enter the MurA enzyme’s active site. Once bound, fosfomycin forms a stable covalent bond with a cysteine residue, permanently blocking the enzyme’s function. This attachment stops the production of foundational building blocks, causing the bacterial cell to lose structural integrity and undergo lysis. The drug gains entry into the bacterial cell by utilizing existing nutrient transporters, such as the GlpT (glycerol-3-phosphate) and UhpT (glucose-6-phosphate) uptake systems.
Bacterial Strategies for Resistance
Bacteria, including P. aeruginosa, counteract fosfomycin’s action through three main strategies. The first involves enzymatic inactivation of the drug, primarily through the production of Fos enzymes. P. aeruginosa inherently expresses a chromosomal FosA enzyme, a metalloenzyme that chemically modifies fosfomycin by conjugating it with glutathione. This modification opens the antibiotic’s epoxide ring, rendering the drug inactive and unable to covalently bind to MurA.
A second mechanism involves alterations in the drug uptake systems. In P. aeruginosa, fosfomycin uptake is mediated almost exclusively by the GlpT transporter. Mutations in the glpT gene lead to a loss of function, preventing the antibiotic from reaching its MurA target inside the cell. This reduced permeability is a common way P. aeruginosa develops acquired resistance, as GlpT is the only functional entry pathway available in this species.
The third strategy involves modifying the MurA target enzyme itself, often through point mutations within the murA gene. These mutations change the enzyme’s active site structure, reducing its binding affinity for fosfomycin without eliminating its natural function. Resistance genes like fosA can also be transferred horizontally via plasmids between different bacteria, increasing the spread of resistance.
Current Clinical Use Against Difficult Infections
The clinical application of fosfomycin against P. aeruginosa is primarily reserved for severe, systemic infections caused by multidrug-resistant strains. The oral formulation is commonly used for uncomplicated urinary tract infections (UTIs) because it achieves high concentrations in the urine. However, systemic P. aeruginosa infections, such as pneumonia, bacteremia, or osteomyelitis, require the intravenous (IV) formulation to achieve therapeutic concentrations in the blood and deep tissues. The IV drug is often favored because of its favorable distribution properties, allowing it to penetrate deep-seated infections.
Fosfomycin is rarely administered as a monotherapy for severe P. aeruginosa infections due to the high risk of rapid resistance development during treatment. Instead, it is typically used as part of a combination regimen with other antipseudomonal antibiotics, such as beta-lactams, aminoglycosides, or colistin. This combination approach leverages the synergistic effect observed when fosfomycin is paired with other classes of drugs. For example, studies have shown that combining fosfomycin with a carbapenem like meropenem significantly enhances bacterial killing and suppresses the emergence of drug-resistant mutants. The drug also demonstrates anti-biofilm activity, particularly when used in combination with other agents, which is beneficial in treating chronic infections.