Fosfomycin

Introduction: chemical and physical properties

Fosfomycin ( (1R,2S)-(-)-2-methyl-1,2-epoxypropyl-1-fosfonic acid or just L -cis -1,2 epoxypropyl fosfonic acid) is a natural antibiotic provided of broad spectrum activity isolated from species of Streptomyces Fradiae.

Is now made by total chemical synthesis. It is a very simple and efficient industrial process illustrated below.

The molecule shows two acidic hydrogens (phosphonic group) with pKa1 = 2,5 and pKa2=7,5. It follows that at a physiological pH value it exists predominantly as a monoanion with a not negligible percentage of dianion.

The stereochemistry of the molecule is well defined and fundamental for the interaction with the target.

Being fosfomycin an extremely tiny molecule (low MW) and hydrophilic as well, just like cycloserine it won't have any problem in passing through the porins of Gram- bacteria. Its uptake is mediated by organic phosphate carrier (active transport, requires ATP).

It is an handy drug which can be administered in pediatrics and pregnancy also.

Pharmacokinetic

Fosfomycin can be administered intravenously as sodium salt (more soluble) or via OS as calcium (Ca2+) or  trometamol salt.

Shows good absorption and distribution (does not bond plasma proteins). It is eliminated with urine (unalterated).

Half-life: 5h approximately

Pharmacodynamic (mechanism of action)

BACTERICYDAL on Gram+ and Gram- bacteria (broad spectrum) Pseudomonas also.

Fosfomycin inibits the biogenesis of the main constituent of bacterial cell wall: pepridoglycan. Acts on the enzyme enolpyruvate  transferase, via a non - competitive mechanism (a covalent bond forms).

Enolpyruvate  transferase is a bacterial enzyme (not present in human, we don't have peptidoglycan!) that catalyzes the incorporation reaction of phosphoenolpiruvic acid in N-acetyl glucosamine (NAG), first step in the biosynthetic pathway of N-acetyl muramic acid (NAM). Keep in mind that NAG and NAM form a dimer that is the fundamental (glucidic) constituent unit of peptidoglycan. Without N-acetyl muramic acid the cell wall synthesis is therefore impossible. In this case also the arrest of cell wall synthesis brings to the death of the bacterial cell by osmotic lysis.

Fosfomycin interferes with the first step of the reaction shown just above.

More specifically, fosfomycin mimics the phosphoenolpiruvic acid and gives a covalent adduct with the enzyme phosphoenolpyruvate transferase.

The actual reactive group is a thiol  (belonging to a cysteine of the transferase). It attacks the most reactive position of the oxyrane ring (2), that has a partial positive charge (δ+) and is less hindered than 1. The reaction is pushed forward thanks the high steric tension of the three membered ring, which is indeed easily opened by the nucleophile.

Synthesis 

The industrial chemical synthesis below is commentated and explained step by step in details at the following link: Fosfomycin synthesis.

Clinical use 

Fosfomycin finds clinical employment above all in the treatment of infections related to the urinary  (prophylaxis also) and gastroenteric tract. Resistance occurs quicly because of mutations (on genes encoded by chromosomes and plasmids) who determine the missed uptake of the drug (thus at a level of the active transport mediated by membrane carrier). For this reason fosfomycin (commercially Monurol or Monuril) is used only in brief duration therapies.

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