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 protozoaCryptosporidium andToxoplasma as well as the fungusCandida glabrata . A comparison of the structures of DHFR from the fungal speciesCandida glabrata andPneumocystis suggests that the compounds may also potently inhibitPneumocystis DHFR.