Disease relevance of fosmidomycin

• Inhibition of the MEP pathway with fosmidomycin abolished IspE rescue of Hc1-expressing E. coli [1].
• Fosmidomycin plus clindamycin was shown to be efficacious in the treatment of uncomplicated Plasmodium falciparum malaria in a small cohort of pediatric patients aged 7 to 14 years, but more data, including data on younger children with less antiparasitic immunity, are needed to determine the potential value of this new antimalarial combination [2].
• It has been demonstrated that fosmidomycin has good tolerability and rapid onset of action, but late recrudescences preclude its use alone; in vitro, clindamycin has been shown to act synergistically with fosmidomycin against Plasmodium falciparum [3].
• FR-31564 inhibited a number of E. coli, K. pneumoniae, and some Pseudomonas aeruginosa strains resistant to the other agents [4].
• Synergy between fosmidomycin and penicillins or cephalosporins was found for 37 to 52% of the Enterobacteriaceae tested [5].

High impact information on fosmidomycin

• As a response to fosmidomycin treatment, a transient increase in sterol levels was observed, whereas chlorophyll and carotenoid amounts decreased dramatically when compared with controls [6].
• Structural basis of fosmidomycin action revealed by the complex with 2-C-methyl-D-erythritol 4-phosphate synthase (IspC). Implications for the catalytic mechanism and anti-malaria drug development [7].
• Here, we present the crystal structure of Escherichia coli IspC in complex with manganese and fosmidomycin at 2.5 A resolution [7].
• We also show the pharmacological complementation of the enhanced-resistance phenotype of csb3 plants with fosmidomycin, an inhibitor of the MEP pathway, and propose that CSB3 represents a point of metabolic convergence modulating the magnitude of SA-mediated disease resistance to biotrophic pathogens [8].
• The key enzyme in the non-mevalonate pathway of isoprenoid biosynthesis, 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR) has been shown to be the target enzyme of fosmidomycin, an antimalarial, antibacterial and herbicidal compound [9].

Chemical compound and disease context of fosmidomycin

• Fosmidomycin plus clindamycin was generally well tolerated, but relatively high rates of treatment-associated neutropenia (8/51 [16%]) and falls of hemoglobin concentrations of > or =2 g/dl (7/51 [14%]) are of concern [2].
• Furthermore, fosfomycin resistance plasmids did not confer on E. coli cells resistance to the novel antibiotic FR-31564, which is incorporated by the same transport systems as fosfomycin [10].
• This transformant could grow in the presence of fosmidomycin, a potent and specific inhibitor of the nonmevalonate pathway, indicating that the mevalonate pathway, intrinsically absent in E. coli, is operating in the E. coli transformant [11].
• The mechanism of action of fosmidomycin (FR-31564), a phosphonic acid containing antibiotic, was examined against Escherichia coli, Micrococcus luteus and other bacteria [12].

Biological context of fosmidomycin

• The specificity constant of Rv2780c in the forward direction is 1.5 x 10(6) M(-1) min(-1), and the reaction is inhibited by fosmidomycin, with a 50% inhibitory concentration of 310 nM [13].
• A gene conferring resistance to fosmidomycin (Fs) was cloned from the gene pool of a wild-type strain of Escherichia coli [14].
• We concluded that the slow tight-binding behaviour, and perhaps also cooperativity, are mediated by significant reorganisation of the active site upon fosmidomycin binding [15].
• In leaves whose monoterpene synthesis had been inhibited by fosmidomycin, ozone rapidly and significantly inhibited photosynthesis and increased the production of hydrogen peroxide and malonyldialdehyde [16].

Anatomical context of fosmidomycin

• Inhibition of DXR activity by fosmidomycin showed that plastid isoprenoid biosynthesis is required for tomato fruit carotenogenesis but not for other ripening processes [17].

Associations of fosmidomycin with other chemical compounds

• A very low (13)C labeling was found in the DMAPP pool and in the residual isoprene emission of leaves previously fed with fosmidomycin to inhibit isoprene formation [18].
• In vitro and in vivo synergy of fosmidomycin, a novel antimalarial drug, with clindamycin [19].
• In vitro and in vivo antibacterial activity of FR-31564, a phosphonic acid antimicrobial agent [4].
• Synthesis and biological evaluation of cyclopropyl analogues of fosmidomycin as potent Plasmodium falciparum growth inhibitors [20].
• In this work, we have generated transgenic Arabidopsis thaliana plants with altered DXS and DXR enzyme levels, as estimated from their resistance to clomazone and fosmidomycin, respectively [21].

Gene context of fosmidomycin

• E. coli glpT mutants were resistant to fosfomycin and also to fosmidomycin [22].
• The antibiotic fosmidomycin specifically inhibits this DXR enzyme activity [23].
• 1-Deoxy-D-xylulose 5-phosphate reductoisomerase (IspC) from Mycobacterium tuberculosis: towards understanding mycobacterial resistance to fosmidomycin [13].
• Furthermore, the complete arrest of tomato seedling development using fosmidomycin confirms a key role of the MEP pathway in plant development [17].
• However, over the experimental period, fosmidomycin did not affect concentrations of compounds that are formed from chloroplastic isoprenoids and that might have conferred antioxidant protection, either directly (carotenoids) or indirectly (chlorophylls, xanthophylls) [16].

Analytical, diagnostic and therapeutic context of fosmidomycin

• This target has been characterized as having potential in the treatment of malaria with fosmidomycin, an established DXR inhibitor, presently in clinical trials [24].
• In the multiple-dose study, there was no accumulation of fosmidomycin in the serum even after 21 consecutive intramuscular dosings of 1 g every 6 h or 29 consecutive 0.5-h drip infusions of 2 g every 6 h [25].
• When a fully resistant strain was exposed to fosmidomycin, bacterial growth was also suppressed for 13 h or more, even when the peak concentration achieved was below the conventionally determined minimum inhibitory concentration [26].
• Bioassay for determination of fosmidomycin in plasma and urine: Application for pharmacokinetic dose optimisation [27].
• Determination of fosmidomycin in human serum and urine by capillary electrophoresis [28].

References