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Bacterial Folate Synthesis Inhibition Module

Module bacterial_folate_synthesis_inhibition 2 disorders Pathograph 2
A conserved antibacterial drug-mechanism module representing the bacterial de novo tetrahydrofolate (THF) biosynthesis pathway, which bacteria must build themselves because — unlike humans — they cannot take up preformed folate from the diet. Two sequential enzymes are antibacterial targets: dihydropteroate synthase (DHPS), inhibited by the sulfonamides (sulfamethoxazole, dapsone), and dihydrofolate reductase (DHFR), inhibited by trimethoprim. Blocking THF synthesis starves the cell of the one-carbon donors needed for nucleotide and amino-acid synthesis. Combining a DHPS inhibitor with a DHFR inhibitor (co-trimoxazole = trimethoprim-sulfamethoxazole) produces sequential blockade with synergistic, bactericidal activity. DHPS is unique to prokaryotes, giving selectivity. This module defines the mechanism-of-action design pattern for antifolate treatments: conforming entries link a treatment to the DHPS/DHFR target via target_mechanisms.
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Pathophysiology Nodes

2
2 shared nodes are defined in this module.
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Cell Types

0
No cell types are annotated for this module.
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Biological Processes

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Tetrahydrofolate Biosynthetic Process GO:0046654 Response to Antibiotic GO:0046677
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Notes

Antibacterial drug-mechanism module, not a specific disease. Disorder entries reference nodes via conforms_to (e.g., "bacterial_folate_synthesis_inhibition#Bacterial Tetrahydrofolate Synthesis (Antifolate Target)"), and their sulfonamide/trimethoprim/dapsone treatments point at that node via target_mechanisms. Key conformance / treatment target: "Bacterial Tetrahydrofolate Synthesis (Antifolate Target)". Dapsone is a DHPS inhibitor and conforms here (e.g. leprosy). Nodes are druggable steps, not individual drugs.
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Used By Disorder Entries

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Leprosy via Mycobacterial Tetrahydrofolate Synthesis (Dapsone/DHPS Target) → Bacterial Tetrahydrofolate Synthesis (Antifolate Target)
Whipple Disease via Tropheryma Tetrahydrofolate Synthesis (TMP-SMX Target) → Bacterial Tetrahydrofolate Synthesis (Antifolate Target)
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Pathograph

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Pathograph: causal mechanism network for Bacterial Folate Synthesis Inhibition Module Interactive directed graph showing how this shared module's pathophysiology nodes connect.
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Pathophysiology

2
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.
Tetrahydrofolate Biosynthetic Process GO:0046654
Used by disorders
Leprosy as Mycobacterial Tetrahydrofolate Synthesis (Dapsone/DHPS Target)
Whipple Disease as Tropheryma Tetrahydrofolate Synthesis (TMP-SMX Target)
Downstream
  • Antifolate Target Resistance Drug-insensitive DHPS/DHFR variants protect the pathway, escaping antifolate therapy.
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.
Response to Antibiotic GO:0046677