Antimicrobial dihydrofolate reductase inhibitors achievements and future options: Review

Despite all progress made in the fight against infections caused by bacteria, fungi, protozoa or viruses, there is a need for more and new active agents. Intensive efforts are currently directed against many new and attractive targets, and are hoped to result in new useful agents. The opportunities offered by some known and validated targets are, however, by far not exhausted. Dihydrofolate reductase (DHFR, EC 1.5.1.3) attracted much attention over several decades, which yielded several useful agents. There are excellent chances for new drugs in this field, and they are thought to increase by limiting the spectrum of activity. Whereas trimethoprim seems to present the optimum which can be achieved for a broad spectrum antibacterial agent, specific agents could probably be designed for well defined groups or specific organisms, such as staphylococci among the bacteria, or for a number of parasites, such as Plasmodium falciparum, the fungus Pneumocystis carinii, and several protozoa, such as Trypanosoma, Toxoplasma, and others. This would even extend to herbicides or specific plant pathogens. Achievements and current efforts directed against new DHFR-inhibitors are reviewed, considering only the most recent literature.