Editing Trimethoprim (section)

==Mechanism of action==
[[File:Wild-type staphylococcus aureus DHFR in complex with NADPH and trimethoprim.gif|thumb|upright=1.25|''Staphylococcus aureus'' DHFR in complex with NADPH and trimethoprim PDB entry {{PDBe|2W9G}}<ref>{{cite journal | vauthors = Heaslet H, Harris M, Fahnoe K, Sarver R, Putz H, Chang J, Subramanyam C, Barreiro G, Miller JR | title = Structural comparison of chromosomal and exogenous dihydrofolate reductase from Staphylococcus aureus in complex with the potent inhibitor trimethoprim | journal = Proteins | volume = 76 | issue = 3 | pages = 706–717 | date = August 2009 | pmid = 19280600 | doi = 10.1002/prot.22383 | s2cid = 1373618 }}</ref>]]
Trimethoprim binds to [[dihydrofolate reductase]] and inhibits the reduction of [[dihydrofolic acid]] (DHF) to [[tetrahydrofolic acid]] (THF).<ref name = drugs82/> THF is an essential precursor in the thymidine synthesis pathway and interference with this pathway inhibits bacterial DNA synthesis.<ref name = drugs82/> Trimethoprim's inhibitory activity for bacterial dihydrofolate reductase is sixty thousand times greater than for human dihydrofolate reductase.<ref>{{cite journal | vauthors = Burchall JJ | title = Mechanism of action of trimethoprim-sulfamethoxazole. II | journal = The Journal of Infectious Diseases | volume = 128 | pages = Suppl: 437-Suppl: 441 | date = November 1973 | pmid = 4585969 | doi = 10.1093/infdis/128.Supplement_3.S437 | ref = TMP1 | jstor = 30105875 }}</ref> [[Sulfamethoxazole]] inhibits [[dihydropteroate synthase]], an enzyme involved further upstream in the same pathway.<ref name = drugs82/> [[Trimethoprim/sulfamethoxazole|Trimethoprim and sulfamethoxazole]] are commonly used in combination due to possible synergistic effects, and reduced development of resistance.<ref name = drugs82>{{cite journal | vauthors = Brogden RN, Carmine AA, Heel RC, Speight TM, Avery GS | title = Trimethoprim: a review of its antibacterial activity, pharmacokinetics and therapeutic use in urinary tract infections | journal = Drugs | volume = 23 | issue = 6 | pages = 405–430 | date = June 1982 | pmid = 7049657 | doi = 10.2165/00003495-198223060-00001 | s2cid = 21806926 }}</ref> This benefit has been questioned.<ref name=Brumfitt1993>{{cite journal | vauthors = Brumfitt W, Hamilton-Miller JM | title = Reassessment of the rationale for the combinations of sulphonamides with diaminopyrimidines | journal = Journal of Chemotherapy | volume = 5 | issue = 6 | pages = 465–469 | date = December 1993 | pmid = 8195839 | doi = 10.1080/1120009X.1993.11741097 }}</ref>
[[Image:THFsynthesispathway.png|class=skin-invert-image|[[Tetrahydrofolate]] synthesis pathway|thumb|none|upright=1.25]]