title: Towards new antifolates targeting eukaryotic opportunistic infections.
abstract: Trimethoprim, an antifolate commonly prescribed in combination with sulfamethoxazole, potently inhibits several prokaryotic species of dihydrofolate reductase (DHFR). However, several eukaryotic pathogenic organisms are resistant to trimethoprim, preventing its effective use as a therapeutic for those infections. We have been building a program to reengineer trimethoprim to more potently and selectively inhibit eukaryotic species of DHFR as a viable strategy for new drug discovery targeting several opportunistic pathogens. We have developed a series of compounds that exhibit potent and selective inhibition of DHFR from the parasitic protozoa Cryptosporidium and Toxoplasma as well as the fungus Candida glabrata. A comparison of the structures of DHFR from the fungal species Candida glabrata and Pneumocystis suggests that the compounds may also potently inhibit Pneumocystis DHFR.
authors.affiliation: Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, USA.
authors.forename: Jieying
authors.initials: J
authors.lastname: Liu
authors.forename: David B
authors.initials: DB
authors.lastname: Bolstad
authors.forename: Erin S D
authors.initials: ES
authors.lastname: Bolstad
authors.forename: Dennis L
authors.initials: DL
authors.lastname: Wright
authors.forename: Amy C
authors.initials: AC
authors.lastname: Anderson
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D041221:Candida glabrata / Q000737:chemistry / Q000201:enzymology; D015195:Drug Design; D005493:Folic Acid Antagonists / Q000737:chemistry / Q000494:pharmacology*; D005656:Fungal Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D009894:Opportunistic Infections / Q000188:drug therapy* / Q000382:microbiology / Q000469:parasitology; D011010:Pneumocystis / Q000737:chemistry / Q000201:enzymology; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D016415:Sequence Alignment; D013329:Structure-Activity Relationship; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry* / Q000378:metabolism; D014122:Toxoplasma / Q000737:chemistry / Q000201:enzymology; D014295:Trimethoprim / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D005493:Folic Acid Antagonists; D005656:Fungal Proteins; D015800:Protozoan Proteins; D014295:Trimethoprim; D013762:Tetrahydrofolate Dehydrogenase