Fosfomycin
Encyclopedia
Fosfomycin (trade names Monurol, Monuril) is a broad-spectrum antibiotic
produced by certain Streptomyces
species.
s, where it is usually administered as a single oral megadose.
The drug is well tolerated and has a low incidence of harmful side-effects. However, development of bacterial resistance under therapy is a frequent occurrence and makes fosfomycin unsuitable for sustained therapy of severe infections.
Additional uses have been proposed. The global problem of advancing antimicrobial resistance has led to a renewed interest in its use more recently.
in peptidoglycan
biosynthesis, namely the ligation of phosphoenolpyruvate
(PEP) to the 3'-hydroxyl group of UDP-N-acetylglucosamine. This pyruvate moiety provides the linker that bridges the glycan and peptide portion of peptidoglycan. Fosfomycin is a PEP analog that inhibits MurA by alkylating
an active site cysteine
residue (Cys 115 in the Escherichia coli
enzyme).
Fosfomycin enters the bacterial cell through the glycerophosphate transporter.
from Streptomyces
fradiae has been cloned and sequenced and the heterologous production of fosfomycin in Streptomyces
lividans has been achieved by Ryan Woodyer of the Huimin Zhao
and Wilfred van der Donk research groups.
s conferring resistance to fosfomycin have also been identified and are encoded both chromosomally
and on plasmid
s.
for FosA, cysteine
for FosB, and water for FosX.
and adds a phosphate
group to fosfomycin, thus altering its properties and making the drug ineffective.
Broad-spectrum antibiotic
The term broad-spectrum antibiotic refers to an antibiotic that acts against a wide range of disease-causing bacteria. A broad-spectrum antibiotic acts against both Gram-positive and Gram-negative bacteria, in contrast to a narrow-spectrum antibiotic, which is effective against specific families of...
produced by certain Streptomyces
Streptomyces
Streptomyces is the largest genus of Actinobacteria and the type genus of the family Streptomycetaceae. Over 500 species of Streptomyces bacteria have been described. As with the other Actinobacteria, streptomycetes are gram-positive, and have genomes with high guanine and cytosine content...
species.
Uses
Fosfomycin is indicated in the treatment of urinary tract infectionUrinary tract infection
A urinary tract infection is a bacterial infection that affects any part of the urinary tract. Symptoms include frequent feeling and/or need to urinate, pain during urination, and cloudy urine. The main causal agent is Escherichia coli...
s, where it is usually administered as a single oral megadose.
The drug is well tolerated and has a low incidence of harmful side-effects. However, development of bacterial resistance under therapy is a frequent occurrence and makes fosfomycin unsuitable for sustained therapy of severe infections.
Additional uses have been proposed. The global problem of advancing antimicrobial resistance has led to a renewed interest in its use more recently.
Mechanism of action
Fosfomycin inhibits bacterial cell wall biogenesis by inactivating the enzyme UDP-N-acetylglucosamine-3-enolpyruvyltransferase, also known as MurA. This enzyme catalyzes the committed stepCommitted step
In enzymology, the committed step is an effectively irreversible enzymatic reaction that occurs at a branch point during the biosynthesis of some molecules.-What it means:...
in peptidoglycan
Peptidoglycan
Peptidoglycan, also known as murein, is a polymer consisting of sugars and amino acids that forms a mesh-like layer outside the plasma membrane of bacteria , forming the cell wall. The sugar component consists of alternating residues of β- linked N-acetylglucosamine and N-acetylmuramic acid...
biosynthesis, namely the ligation of phosphoenolpyruvate
Phosphoenolpyruvate
Phosphoenolpyruvic acid , or phosphoenolpyruvate as the anion, is an important chemical compound in biochemistry. It has the high-energy phosphate bond found in living organisms, and is involved in glycolysis and gluconeogenesis...
(PEP) to the 3'-hydroxyl group of UDP-N-acetylglucosamine. This pyruvate moiety provides the linker that bridges the glycan and peptide portion of peptidoglycan. Fosfomycin is a PEP analog that inhibits MurA by alkylating
Alkylation
Alkylation is the transfer of an alkyl group from one molecule to another. The alkyl group may be transferred as an alkyl carbocation, a free radical, a carbanion or a carbene . Alkylating agents are widely used in chemistry because the alkyl group is probably the most common group encountered in...
an active site cysteine
Cysteine
Cysteine is an α-amino acid with the chemical formula HO2CCHCH2SH. It is a non-essential amino acid, which means that it is biosynthesized in humans. Its codons are UGU and UGC. The side chain on cysteine is thiol, which is polar and thus cysteine is usually classified as a hydrophilic amino acid...
residue (Cys 115 in the Escherichia coli
Escherichia coli
Escherichia coli is a Gram-negative, rod-shaped bacterium that is commonly found in the lower intestine of warm-blooded organisms . Most E. coli strains are harmless, but some serotypes can cause serious food poisoning in humans, and are occasionally responsible for product recalls...
enzyme).
Fosfomycin enters the bacterial cell through the glycerophosphate transporter.
Biosynthetic gene cluster
The complete fosfomycin biosynthetic gene clusterGene cluster
A gene cluster is a set of two or more genes that serve to encode for the same or similar products. Because populations from a common ancestor tend to possess the same varieties of gene clusters, they are useful for tracing back recent evolutionary history...
from Streptomyces
Streptomyces
Streptomyces is the largest genus of Actinobacteria and the type genus of the family Streptomycetaceae. Over 500 species of Streptomyces bacteria have been described. As with the other Actinobacteria, streptomycetes are gram-positive, and have genomes with high guanine and cytosine content...
fradiae has been cloned and sequenced and the heterologous production of fosfomycin in Streptomyces
Streptomyces
Streptomyces is the largest genus of Actinobacteria and the type genus of the family Streptomycetaceae. Over 500 species of Streptomyces bacteria have been described. As with the other Actinobacteria, streptomycetes are gram-positive, and have genomes with high guanine and cytosine content...
lividans has been achieved by Ryan Woodyer of the Huimin Zhao
Huimin Zhao
Dr. Huimin Zhao is a Professor of Chemical and Biomolecular Engineering at the University of Illinois, Urbana-Champaign. His research focuses on directed evolution, metabolic engineering, bioinformatics and high throughput technologies....
and Wilfred van der Donk research groups.
Resistance
Mutations that inactivate the non-essential glycerophosphate transporter render bacteria resistant to fosfomycin.Fosfomycin resistance enzymes
EnzymeEnzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
s conferring resistance to fosfomycin have also been identified and are encoded both chromosomally
Chromosome
A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...
and on plasmid
Plasmid
In microbiology and genetics, a plasmid is a DNA molecule that is separate from, and can replicate independently of, the chromosomal DNA. They are double-stranded and, in many cases, circular...
s.
Glyoxalase superfamily enzymes
Three related but mechanistically distinct fosfomycin resistance enzymes (named, FosA, FosB and FosX) function by nucleophilic attack on carbon 1 of fosfomycin. This opens the epoxide ring and renders the drug ineffective. The enzymes differ by the identity of the nucleophile utilized in the reaction: glutathioneGlutathione
Glutathione is a tripeptide that contains an unusual peptide linkage between the amine group of cysteine and the carboxyl group of the glutamate side-chain...
for FosA, cysteine
Cysteine
Cysteine is an α-amino acid with the chemical formula HO2CCHCH2SH. It is a non-essential amino acid, which means that it is biosynthesized in humans. Its codons are UGU and UGC. The side chain on cysteine is thiol, which is polar and thus cysteine is usually classified as a hydrophilic amino acid...
for FosB, and water for FosX.
FosC
FosC utilizes ATPAdenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
and adds a phosphate
Phosphate
A phosphate, an inorganic chemical, is a salt of phosphoric acid. In organic chemistry, a phosphate, or organophosphate, is an ester of phosphoric acid. Organic phosphates are important in biochemistry and biogeochemistry or ecology. Inorganic phosphates are mined to obtain phosphorus for use in...
group to fosfomycin, thus altering its properties and making the drug ineffective.