Fosfomycin [(-)-cis-1,2-epoxypropyl phosphonic acid] was discovered in 1968 as a secondary metabolite of several Streptomyces species (28). It aroused considerable interest, since it was a completely new molecule having antibacterial activity which exhibited relevant properties, such as a broad spectrum, covering many pathogenic and opportunistic gram-positive (Staphylococcus aureus and Streptococcus spp.) and gram-negative (Pseudomonas aeruginosa, Neisseria spp., and members of the family Enterobacteriaceae) bacteria (5, 19, 35, 43, 68). Furthermore, in combination with other antimicrobial agents, it was synergistic (17, 24, 50, 51, 61). Its chemical structure (Fig. 1) (12) presented new features, with a stable epoxide group and a direct carbonphosphorus bond, both of which were necessary for therapeutic activity (12, 34); these features explained the absence of cross-resistance with other antibiotics used in therapy (55). Fosfomycin, acting as a phosphoenolpyruvate analog, irreversibly inhibited phosphoenolpyruvate UDP-N-acetylglucosamine-3-O-enolpyruvyl transferase (enolpyruvyl transferase) (11, 34, 53, 54, 65), an enzyme which catalyzed the first step of peptidoglycan biosynthesis. It has almost no toxicity in humans (18, 28). It does not have an affinity for plasma proteins, in part explaining its lack of induction of allergic reactions (35, 55). Fosfomycin can be administered both parenterally (disodium salt) and orally (calcium, lysine and, more recently, trimethamine salts) (9, 10, 16, 21, 26) and shows excellent penetration into body fluids (15, 21, 52), with renal excretion of the active compound and short clearance times (9, 21, 35). Finally, it is taken up by eucaryotic cells and acts against intracellular parasites (29). Fosfomycin is taken into cells by active transport through the partially constitutive L-a-glycerophosphate uptake system (GlpT), as demonstrated by the finding that GlpT mutants are resistant to fosfomycin (Fo) and that constitutive mutants appear to be hypersusceptible to the drug (34). A secondary transport system, which mediates hexose phosphate uptake (Uhp), can be induced by glucose 6-phosphate. Under such conditions, transport of and susceptibility to fosfomycin by GlpTmutants became comparable to those of wild-type strains (34). Most chromosomally resistant mutants have an impairment in one or both of these uptake systems (33, 34, 60). Mutations that diminish the affinity of fosfomycin for its target enzyme also make cells resistant, although in this case there is a concomitant increase in the Km for phosphoenolpyruvate, resulting in a lower rate of synthesis of peptidoglycan (62). The use of fosfomycin has selected another type of resistant organisms which actively incorporate the drug (27, 37, 45) and have a fully sensitive enolpyruvyl transferase (38),

Plasmid-encoded fosfomycin resistance.

Ruthenium-catalyzed [2 + 2] cycloadditions of bicyclic alkenes with alkynyl phosphonates were investigated. The phosphonate moieties were found to be compatible with the Ru-catalyzed cycloadditions giving the corresponding cyclobutene cycloadducts in low to excellent yield (up to 96%). Alkynyl phosphonates showed lower reactivity than other heteroatom-substituted alkynes such as alkynyl halides, ynamides, alkynyl sulfides, and alkynyl sulfones and required a higher reaction temperature and much longer reaction time.

Ruthenium-catalyzed [2 + 2] cycloadditions of bicyclic alkenes with alkynyl phosphonates.

α-Phosphonozirconacyclopentenes or α-borylzirconacyclopentenes react by bromination, iodination, allylation, and propargylation to generate unique vinyl boronates and vinyl phosphonates not obtainable by other methods. The reaction proceeds in two steps, with both high regio- and stereoselectivity. With the vinyl boronates, the Zr−Csp2 bond is initially cleaved by 1 equiv of electrophile. With the phosphonates, either the Zr−Csp2 bond (allyl bromide, Br2) or the Zr−Csp3 bond (I2, propargyl bromide) may be initially cleaved. The addition of a second equivalent of an electrophile results in disubstitution.

M. Fernández-Ibañez

Papers

Self‐consistent field‐molecular orbital (SCF‐MO) calculations and nuclear magnetic resonance measurements for fosfomycin and related compounds