Patrick J. Cassidy

THE MECHANISM OF ACTION OF FOSFOMYCIN (PHOSPHONOMYCIN)

The discovery of fosfomycin, a new antibiotic produced by strains of Streptomyces, was announced under its former name phosphonomycin by Hendlin and colleagues in 1969.l The chemical structure shown in FIGURE 1 combines two unusual features: an epoxide ring, rare among antibiotics, and a carbon-phosphorus bond which is seen to occur here for the first time among the natural products of the bacteria. Most of the present account concerns the determination of the enzymatic step in cell wall biosynthesis that is ultimately blocked by fosfomycin. We compare in detail the action of that enzyme’s catalytic center upon the antibiotic and its normal substrate. We also describe the role of two stereospecific nutrient transport systems that by mediating the entry and accumulation of fosfomycin comprise the determining factors in the sensitivity of various bacteria to this polar antibiotic. Although the main conclusions of these mechanism of action studies were briefly stated by us in the initial announcement,’, the present publication is the first in which there appears any portion of the original experimental data that support those conclusions. Several reports have appeared from other laboratories 4, and from our own IJ in which certain basic findings and methodology were reproduced in the course of pursuing the independent goals of their studies. Their additional contributions to the understanding of fosfomycin action are cited at appropriate points in the succeeding text.