Bacterial Tetrahydrofolate Synthesis (Antifolate Target)
therapeutic vulnerability
Bacteria synthesize tetrahydrofolate (THF) de novo because they cannot import preformed folate. Two sequential enzymes are drug targets: dihydropteroate synthase (DHPS), the target of the sulfonamides (sulfamethoxazole) and the sulfone dapsone, and dihydrofolate reductase (DHFR), the target of trimethoprim. THF supplies the one-carbon units required for thymidine, purine, and methionine synthesis, so blocking the pathway halts nucleic-acid and protein synthesis. DHPS is unique to prokaryotes, which gives sulfonamides their selectivity; co-trimoxazole combines DHPS and DHFR inhibition for synergistic sequential blockade.
Used by disorders
Leprosy
as Mycobacterial Tetrahydrofolate Synthesis (Dapsone/DHPS Target)
Melioidosis
as B. pseudomallei Tetrahydrofolate Synthesis (TMP-SMX Target)
Nocardiosis
as Nocardia Tetrahydrofolate Synthesis (TMP-SMX Target)
Downstream
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Antifolate Target Resistance
Drug-insensitive DHPS/DHFR variants protect the pathway, escaping antifolate therapy.
Show evidence (2 references)
"The other two enzyme families are involved in the synthesis of tetrahydrofolate (THF), i.e. dihydropteroate synthase (DHPS) and dihydrofolate reductase."
Review establishing DHPS and DHFR in tetrahydrofolate synthesis as the sulfonamide and trimethoprim targets this node represents. Evidence source is OTHER as this is a review article.
"An additional anti-folate target is dihyropteroate synthase (DHPS), which is unique to prokaryotes as they cannot acquire folate through dietary means."
Supports the prokaryote-specific DHPS target and the selectivity basis noted in this node. Evidence source is OTHER as this is a review article.
Antifolate Target Resistance
adaptive escape
Resistance to antifolates is mainly due to horizontal acquisition of genes encoding drug-insensitive variants of the target enzymes — alternative dihydropteroate synthase (sul genes) and dihydrofolate reductase (dfr genes) — and to chromosomal target mutations. This is a common cause of co-trimoxazole failure and shapes its use in susceptibility-guided therapy.
Show evidence (1 reference)
"changes in the structure and protection of antibiotic targets and the direct modification or inactivation of antibiotics."
General review of resistance mechanisms including target alteration — here drug-insensitive DHPS/DHFR variants. Evidence source is OTHER as this is a review article.