Bacterial folic acid metabolism

Bacterial folic acid metabolism is a critical metabolic pathway responsible for the de novo synthesis of tetrahydrofolate (THF), an essential cofactor for one-carbon transfer reactions in prokaryotes [1, 2]. Unlike humans, who lack the enzymes for de novo folate synthesis and must obtain folate through dietary sources, most bacteria utilize a multi-step enzymatic process to convert precursors like para-aminobenzoic acid (pABA) and guanosine triphosphate (GTP) into dihydrofolate and subsequently THF [2, 6]. This pathway is a cornerstone of antimicrobial chemotherapy, as the absence of comparable de novo synthesis in human cells provides a high degree of selectivity for targeting bacterial infections [8, 11]. The pathway contains several key enzymatic nodes, most notably dihydropteroate synthase (DHPS) and dihydrofolate reductase (DHFR), which are targeted by sulfonamides and trimethoprim, respectively [3, 13]. Inhibition of these enzymes leads to the depletion of purine and thymidine precursors, resulting in the cessation of DNA synthesis and bacterial replication—a state often described as "thymineless death" [12]. Although highly effective, the therapeutic utility of targeting this pathway is frequently complicated by the development of antibiotic resistance, often mediated by target site mutations or the acquisition of plasmid-borne genes encoding insensitive enzyme variants [3, 10].

Other names

Bacterial folate biosynthesis pathwayDe novo folate synthesisBacterial folate metabolismBacterial folate biosynthetic pathway

Sequential inhibition of enzymes in the de novo folate synthesis pathway, primarily dihydropteroate synthase (DHPS) and dihydrofolate reductase (DHFR), to prevent the production of tetrahydrofolate.