Fosmidomycin Explained

Fosmidomycin should not be confused with Fosfomycin.

Fosmidomycin is an antibiotic that was originally isolated from culture broths of bacteria of the genus Streptomyces.[1] 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), MTB at 80 nM, and the Francisella enzyme at 99 nM.[2] Several mutations in the E. coli DXP reductoisomerase were found to confer resistance to fosmidomycin.[3] [4]

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 drugs.[5] Indeed, fosmidomycin has been tested in combination treatment with clindamycin for treatment of malaria with favorable results.[6] [7] [8] 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.[9]

Notes and References

  1. Iguchi E, Okuhara M, Kohsaka M, Aoki H, Imanaka H . Studies on new phosphonic acid antibiotics. II. Taxonomic studies on producing organisms of the phosphonic acid and related compounds . The Journal of Antibiotics . 33 . 1 . 19–23 . January 1980 . 7372546 . 10.7164/antibiotics.33.18 . free .
  2. Jawaid S, Seidle H, Zhou W, Abdirahman H, Abadeer M, Hix JH, van Hoek ML, Couch RD . Kinetic characterization and phosphoregulation of the Francisella tularensis 1-deoxy-D-xylulose 5-phosphate reductoisomerase (MEP synthase) . PLOS ONE . 4 . 12 . e8288 . December 2009 . 20011597 . 2788227 . 10.1371/journal.pone.0008288 . 2009PLoSO...4.8288J . free .
  3. Armstrong CM, Meyers DJ, Imlay LS, Freel Meyers C, Odom AR . Resistance to the antimicrobial agent fosmidomycin and an FR900098 prodrug through mutations in the deoxyxylulose phosphate reductoisomerase gene (dxr) . Antimicrobial Agents and Chemotherapy . 59 . 9 . 5511–9 . September 2015 . 26124156 . 4538460 . 10.1128/AAC.00602-15 .
  4. Pines G, Oh EJ, Bassalo MC, Choudhury A, Garst AD, Fankhauser RG, Eckert CA, Gill RT . Genomic Deoxyxylulose Phosphate Reductoisomerase (DXR) Mutations Conferring Resistance to the Antimalarial Drug Fosmidomycin in E. coli . ACS Synthetic Biology . 7 . 12 . 2824–2832 . November 2018 . 30462485 . 10.1021/acssynbio.8b00219 . 6928208 .
  5. Jomaa H, Wiesner J, Sanderbrand S, Altincicek B, Weidemeyer C, Hintz M, Türbachova I, Eberl M, Zeidler J, Lichtenthaler HK, Soldati D, Beck E . Inhibitors of the nonmevalonate pathway of isoprenoid biosynthesis as antimalarial drugs . Science . 285 . 5433 . 1573–6 . September 1999 . 10477522 . 10.1126/science.285.5433.1573 .
  6. Borrmann S, Adegnika AA, Matsiegui PB, Issifou S, Schindler A, Mawili-Mboumba DP, Baranek T, Wiesner J, Jomaa H, Kremsner PG . Fosmidomycin-clindamycin for Plasmodium falciparum Infections in African children . The Journal of Infectious Diseases . 189 . 5 . 901–8 . March 2004 . 14976608 . 10.1086/381785 . free .
  7. Borrmann S, Lundgren I, Oyakhirome S, Impouma B, Matsiegui PB, Adegnika AA, Issifou S, Kun JF, Hutchinson D, Wiesner J, Jomaa H, Kremsner PG . Fosmidomycin plus clindamycin for treatment of pediatric patients aged 1 to 14 years with Plasmodium falciparum malaria . Antimicrobial Agents and Chemotherapy . 50 . 8 . 2713–8 . August 2006 . 16870763 . 1538678 . 10.1128/AAC.00392-06 .
  8. Ruangweerayut R, Looareesuwan S, Hutchinson D, Chauemung A, Banmairuroi V, Na-Bangchang K . Assessment of the pharmacokinetics and dynamics of two combination regimens of fosmidomycin-clindamycin in patients with acute uncomplicated falciparum malaria . Malaria Journal . 7 . 1 . 225 . October 2008 . 18973702 . 2600645 . 10.1186/1475-2875-7-225 . free .
  9. David A. Fidock . 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 . Use of high-density tiling microarrays to identify mutations globally and elucidate mechanisms of drug resistance in Plasmodium falciparum . Genome Biology . 10 . 2 . R21 . February 2009 . 19216790 . 2688282 . 10.1186/gb-2009-10-2-r21 . free .

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