Molecular Pharmacology of the Antibiotic Fosfomycin, an Inhibitor of Peptidoglycan Biosynthesis

The antibiotic fosfomycin is an epoxy-phosphonate natural product with a broad spectrum of antibacterial activity and distinct mechanism of action that has been in clinical use for 50 years. Fosfomycin is an irreversible covalent inhibitor of UDP-GlcNAc enolpyruvyl transferase (MurA), which catalyzes the first committed step in bacterial peptidoglycan biosynthesis. Fosfomycin binds to the active site of MurA in competition with substrate phosphoenolpyruvate (PEP) and undergoes the ring-opening nucleophilic attack of an active-site cysteine. MurA and its related enolpyruvyl transferase, 5-enolpyruvyl-shikimate-3-phosphate (EPSP) synthase (AroA), are the only known enzymes to catalyze the unusual enolpyruvyl transfer from PEP, and each is the target of an important inhibitor. Specifically, MurA is inactivated by fosfomycin, and EPSP synthase (AroA) of the shikimate pathway is the target of the herbicide glyphosate. Commonalities and differences in enzymatic reaction mechanisms of MurA and EPSP synthase provide a molecular rationale for the specificity of their respective inhibitors. With its distinct mode of molecular action and clinical activity against multidrug-resistant bacteria, fosfomycin continues to motivate the discovery and development of novel inhibitors of MurA.