Editing Dihydrofolate reductase (section)

=== Infection ===
Bacteria also need DHFR to grow and multiply and hence inhibitors selective for bacterial DHFR have found application as antibacterial agents.<ref name="pmid16359642"/> Trimethoprim has shown to have activity against a variety of [[Gram-positive]] bacterial pathogens.<ref name="pmid16359642">{{cite journal | vauthors = Hawser S, Lociuro S, Islam K | title = Dihydrofolate reductase inhibitors as antibacterial agents | journal = Biochemical Pharmacology | volume = 71 | issue = 7 | pages = 941–8 | date = March 2006 | pmid = 16359642 | doi = 10.1016/j.bcp.2005.10.052 }}</ref> However, resistance to trimethoprim and other drugs aimed at DHFR can arise due to a variety of mechanisms, limiting the success of their therapeutical uses.<ref name="pmid7583655">{{cite journal | vauthors = Narayana N, Matthews DA, Howell EE, Nguyen-huu X | title = A plasmid-encoded dihydrofolate reductase from trimethoprim-resistant bacteria has a novel D2-symmetric active site | journal = Nature Structural Biology | volume = 2 | issue = 11 | pages = 1018–25 | date = November 1995 | pmid = 7583655 | doi = 10.1038/nsb1195-1018 | s2cid = 11914241 }}</ref><ref name="pmid8762155">{{cite journal | vauthors = Huennekens FM | title = In search of dihydrofolate reductase | journal = Protein Science | volume = 5 | issue = 6 | pages = 1201–8 | date = June 1996 | pmid = 8762155 | pmc = 2143423 | doi = 10.1002/pro.5560050626 }}</ref><ref name="pmid12084458">{{cite journal | vauthors = Banerjee D, Mayer-Kuckuk P, Capiaux G, Budak-Alpdogan T, Gorlick R, Bertino JR | title = Novel aspects of resistance to drugs targeted to dihydrofolate reductase and thymidylate synthase | journal = Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease | volume = 1587 | issue = 2–3 | pages = 164–73 | date = July 2002 | pmid = 12084458 | doi = 10.1016/S0925-4439(02)00079-0 | doi-access = free }}</ref> Resistance can arise from DHFR gene amplification, [[mutations]] in DHFR,<ref>{{cite journal | vauthors = Toprak E, Veres A, Michel JB, Chait R, Hartl DL, Kishony R | title = Evolutionary paths to antibiotic resistance under dynamically sustained drug selection | journal = Nature Genetics | volume = 44 | issue = 1 | pages = 101–5 | date = December 2011 | pmid = 22179135 | pmc = 3534735 | doi = 10.1038/ng.1034 }}</ref><ref>{{cite journal | vauthors = Rodrigues JV, Bershtein S, Li A, Lozovsky ER, Hartl DL, Shakhnovich EI | title = Biophysical principles predict fitness landscapes of drug resistance | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 113 | issue = 11 | pages = E1470-8 | date = March 2016 | pmid = 26929328 | pmc = 4801265 | doi = 10.1073/pnas.1601441113 | bibcode = 2016PNAS..113E1470R | doi-access = free }}</ref> decrease in the uptake of the drugs, among others. Regardless, trimethoprim and [[sulfamethoxazole]] in combination has been used as an antibacterial agent for decades.<ref name="pmid16359642"/>

[[Pyrimethamine]] is a widely used [[antiprotozoal]] agent.<ref name="pmid3125607">{{cite journal | vauthors = Benkovic SJ, Fierke CA, Naylor AM | title = Insights into enzyme function from studies on mutants of dihydrofolate reductase | journal = Science | volume = 239 | issue = 4844 | pages = 1105–10 | date = March 1988 | pmid = 3125607 | doi = 10.1126/science.3125607 | bibcode = 1988Sci...239.1105B }}</ref>

Other classes of compounds that target DHFR in general, and bacterial DHFRs in particular, belong to the classes such as diaminopteridines, diaminotriazines, diaminopyrroloquinazolines, stilbenes, chalcones, deoxybenzoins, diaminoquinazolines, diaminopyrroloquinazolines, to name but a few.

==== Potential anthrax treatment ====
[[File:Structural alignment of ba sa ec sp dhfr.png|thumb|class=skin-invert-image|[[Structural alignment]] of chromosomal (Type I) dihydrofolate reductase from ''Bacillus anthracis'' (BaDHFR), ''Staphylococcus aureus'' (SaDHFR), ''Escherichia coli'' (EcDHFR), and ''Streptococcus pneumoniae'' (SpDHFR)]]

Dihydrofolate reductase from ''[[Bacillus anthracis]]'' (BaDHFR) is a validated drug target in the treatment of the infectious disease, anthrax. BaDHFR is less sensitive to [[trimethoprim]] analogs than is dihydrofolate reductase from other species such as ''[[Escherichia coli]]'', ''[[Staphylococcus aureus]]'', and ''[[Streptococcus pneumoniae]]''. A structural alignment of dihydrofolate reductase from all four species shows that only BaDHFR has the combination [[phenylalanine]] and [[tyrosine]] in positions 96 and 102, respectively.

BaDHFR's resistance to [[trimethoprim]] analogs is due to these two residues (F96 and Y102), which also confer improved kinetics and catalytic efficiency.<ref name="pmid20882962">{{cite journal | vauthors = Beierlein JM, Karri NG, Anderson AC | title = Targeted mutations of Bacillus anthracis dihydrofolate reductase condense complex structure−activity relationships | journal = Journal of Medicinal Chemistry | volume = 53 | issue = 20 | pages = 7327–36 | date = October 2010 | pmid = 20882962 | pmc = 3618964 | doi = 10.1021/jm100727t }}</ref> Current research uses active site mutants in BaDHFR to guide lead optimization for new antifolate inhibitors.<ref name="pmid20882962"/>