Towards new antifolates targeting eukaryotic opportunistic infections.
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.
Liu
Jieying
J
Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, USA.
Bolstad
David B
DB
Bolstad
Erin S D
ES
Wright
Dennis L
DL
Anderson
Amy C
AC
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*
D005493:Folic Acid Antagonists; D005656:Fungal Proteins; D015800:Protozoan Proteins; D014295:Trimethoprim; D013762:Tetrahydrofolate Dehydrogenase