Folate Biosynthesis – Reappraisal of Old and Novel Targets in the Search for New Antimicrobials

Folate biosynthesis remains a key target for antimicrobial therapy. Folate is an essential vitamin (vitamin B9) that is required for many one-carbon transfer reactions and is a critical precursor for the biosynthesis of purines, pyrimidines, and amino acids. Unlike higher eukaryotes that scavenge preformed folates, prokaryotic and lower eukaryotic microorganisms are dependent on several enzymes for the de novo biosynthesis of folate. One of these enzymes, dihydropteroate synthase (DHPS), is the target of the first chemically-synthesized antimicrobial agents, the sulfadrugs, which date back to the 1940s. Others are essential enzymes that remain to be explored as drug targets. Resistance to the sulfadrugs rapidly emerges due to the ability of the microbe to alter its susceptibility to the drug by various means. Recently a number of new structures of the enzymes in the pathway has become available. We review the recent literature relating to these targets (the enzymes: GTP cyclohydrolase (GTP-CH); 7,8-dihydroneopterin aldolase (DHNA), 6-hydroxymethyl7,8-dihydropterin pyrophosphokinase (HPPK), dihydropteroate synthase (DHPS), dihydrofolate synthase (DHFS)), their mode of action and how current drugs may modulate this on a structural level. Furthermore, these data advance our understanding of the emergence of drug resistance and may aid efforts and play a major role in the design of new, more effective compounds as antimicrobial agents. To this end we also review the recent literature in the development of inhibitors of these enzymes. Future progress in this key area has the potential to benefit the war against devastating organisms such as drug-resistant Staphylococcus aureus and Plasmodium falciparum.