Fosmidomycin

{{Short description|Chemical compound}} {{distinguish|Fosfomycin}} {{Drugbox | Verifiedfields = changed | verifiedrevid = 461113697 | IUPAC_name = 3-[Formyl(hydroxy)amino]propylphosphonic acid | image = Fosmidomycin_.svg | image_class = skin-invert-image | alt = Structural formula of fosmidomycin | image2 = Fosmidomycin 3D ball.png | image_class2 = bg-transparent | alt2 = Ball-and-stick model of the fosmidomycin molecule | width = 240

| CAS_number_Ref = {{cascite|changed|??}} | CAS_number = 66508-53-0 | ATC_prefix = none | PubChem = 572 | DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank = DB02948 | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID = 555 | UNII_Ref = {{fdacite|correct|FDA}} | UNII = 5829E3D9I9 | ChEBI_Ref = {{ebicite|correct|EBI}} | ChEBI = 443725 | ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL = 203125

| C=4 | H=10 | N=1 | O=5 | P=1 | smiles = O=P(O)(O)CCCN(O)C=O | StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI = 1S/C4H10NO5P/c6-4-5(7)2-1-3-11(8,9)10/h4,7H,1-3H2,(H2,8,9,10) | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey = GJXWDTUCERCKIX-UHFFFAOYSA-N }} '''Fosmidomycin''' is an [[antibiotic]] that was originally isolated from culture broths of bacteria of the genus ''[[Streptomyces]]''.<ref>{{cite journal | vauthors = Iguchi E, Okuhara M, Kohsaka M, Aoki H, Imanaka H | title = Studies on new phosphonic acid antibiotics. II. Taxonomic studies on producing organisms of the phosphonic acid and related compounds | journal = The Journal of Antibiotics | volume = 33 | issue = 1 | pages = 19–23 | date = January 1980 | pmid = 7372546 | doi = 10.7164/antibiotics.33.18 | doi-access = free }}</ref> It specifically inhibits [[DXP reductoisomerase]], a key enzyme in the [[non-mevalonate pathway]] of [[isoprenoid]] biosynthesis. It is a structural analogue of [[2-C-methyl-D-erythrose 4-phosphate]]. It inhibits the ''[[E. coli]]'' enzyme with a KI value of 38 nM (4), [[Magnetotactic bacteria|MTB]] at 80 nM, and the ''[[Francisella]]'' enzyme at 99 nM.<ref name="pmid20011597">{{cite journal | vauthors = Jawaid S, Seidle H, Zhou W, Abdirahman H, Abadeer M, Hix JH, van Hoek ML, Couch RD | title = Kinetic characterization and phosphoregulation of the Francisella tularensis 1-deoxy-D-xylulose 5-phosphate reductoisomerase (MEP synthase) | journal = PLOS ONE | volume = 4 | issue = 12 | article-number = e8288 | date = December 2009 | pmid = 20011597 | pmc = 2788227 | doi = 10.1371/journal.pone.0008288 | bibcode = 2009PLoSO...4.8288J | doi-access = free }}</ref> Several mutations in the ''E. coli'' [[DXP reductoisomerase]] were found to confer resistance to fosmidomycin.<ref>{{cite journal | vauthors = Armstrong CM, Meyers DJ, Imlay LS, Freel Meyers C, Odom AR | title = Resistance to the antimicrobial agent fosmidomycin and an FR900098 prodrug through mutations in the deoxyxylulose phosphate reductoisomerase gene (dxr) | journal = Antimicrobial Agents and Chemotherapy | volume = 59 | issue = 9 | pages = 5511–9 | date = September 2015 | pmid = 26124156 | pmc = 4538460 | doi = 10.1128/AAC.00602-15 }}</ref><ref>{{cite journal | vauthors = Pines G, Oh EJ, Bassalo MC, Choudhury A, Garst AD, Fankhauser RG, Eckert CA, Gill RT | title = Genomic Deoxyxylulose Phosphate Reductoisomerase (DXR) Mutations Conferring Resistance to the Antimalarial Drug Fosmidomycin in E. coli | journal = ACS Synthetic Biology | volume = 7 | issue = 12 | pages = 2824–2832 | date = November 2018 | pmid = 30462485 | doi = 10.1021/acssynbio.8b00219 | pmc = 6928208 }}</ref>

==Use in malaria==

The discovery of the [[non-mevalonate pathway]] in [[malaria parasites]] has indicated the use of fosmidomycin and other such inhibitors as [[Antimalarial drug|antimalarial]] drugs.<ref name="Jomaa1999">{{cite journal | vauthors = Jomaa H, Wiesner J, Sanderbrand S, Altincicek B, Weidemeyer C, Hintz M, Türbachova I, Eberl M, Zeidler J, Lichtenthaler HK, Soldati D, Beck E | title = Inhibitors of the nonmevalonate pathway of isoprenoid biosynthesis as antimalarial drugs | journal = Science | volume = 285 | issue = 5433 | pages = 1573–6 | date = September 1999 | pmid = 10477522 | doi = 10.1126/science.285.5433.1573 }}</ref> Indeed, fosmidomycin has been tested in combination treatment with [[clindamycin]] for treatment of [[malaria]] with favorable results.<ref name="Borrmann2004">{{cite journal | vauthors = Borrmann S, Adegnika AA, Matsiegui PB, Issifou S, Schindler A, Mawili-Mboumba DP, Baranek T, Wiesner J, Jomaa H, Kremsner PG | title = Fosmidomycin-clindamycin for Plasmodium falciparum Infections in African children | journal = The Journal of Infectious Diseases | volume = 189 | issue = 5 | pages = 901–8 | date = March 2004 | pmid = 14976608 | doi = 10.1086/381785 | doi-access = free }}</ref><ref name="Borrmann2006">{{cite journal | vauthors = Borrmann S, Lundgren I, Oyakhirome S, Impouma B, Matsiegui PB, Adegnika AA, Issifou S, Kun JF, Hutchinson D, Wiesner J, Jomaa H, Kremsner PG | title = Fosmidomycin plus clindamycin for treatment of pediatric patients aged 1 to 14 years with Plasmodium falciparum malaria | journal = Antimicrobial Agents and Chemotherapy | volume = 50 | issue = 8 | pages = 2713–8 | date = August 2006 | pmid = 16870763 | pmc = 1538678 | doi = 10.1128/AAC.00392-06 }}</ref><ref name="Ruangweerayut2008">{{cite journal | vauthors = Ruangweerayut R, Looareesuwan S, Hutchinson D, Chauemung A, Banmairuroi V, Na-Bangchang K | title = Assessment of the pharmacokinetics and dynamics of two combination regimens of fosmidomycin-clindamycin in patients with acute uncomplicated falciparum malaria | journal = Malaria Journal | volume = 7 | issue = 1 | article-number = 225 | date = October 2008 | pmid = 18973702 | pmc = 2600645 | doi = 10.1186/1475-2875-7-225 | doi-access = free }}</ref> It has been shown that an increase in copy number of the target enzyme ([[DXP reductoisomerase]]) correlates with ''[[in vitro]]'' fosmidomycin resistance in the lethal [[malaria]] parasite, ''[[Plasmodium falciparum]]''.<ref name="Dharia2009">{{cite journal|author13-link=David A. Fidock | vauthors = Dharia NV, Sidhu AB, Cassera MB, Westenberger SJ, Bopp SE, Eastman RT, Plouffe D, Batalov S, Park DJ, Volkman SK, Wirth DF, Zhou Y, Fidock DA, Winzeler EA | title = Use of high-density tiling microarrays to identify mutations globally and elucidate mechanisms of drug resistance in Plasmodium falciparum | journal = Genome Biology | volume = 10 | issue = 2 | pages = R21 | date = February 2009 | pmid = 19216790 | pmc = 2688282 | doi = 10.1186/gb-2009-10-2-r21 | doi-access = free }}</ref>

== References == {{reflist}}

[[Category:Antibiotics]] [[Category:Oxidoreductase inhibitors]] [[Category:Phosphonic acids]]