Sulphonamides and trimethoprim: sequential blockade of bacterial folate synthesis
Sulphonamides and trimethoprim block two consecutive steps in the pathway bacteria use to make folate, a vitamin-derived molecule that cells need to build DNA.
Remember
Sulphonamides block dihydropteroate synthase, an early enzyme in the pathway, and trimethoprim blocks dihydrofolate reductase, a later enzyme that makes tetrahydrofolate (the active form of folate), so bacteria cannot make the building blocks of DNA.
Memory aid
two-step assembly line for folate
The sulphonamide stops step one and trimethoprim stops step two, so blocking both steps does far more harm to the bacteria than blocking one.
Bacteria cannot take up ready-made folate, so they must make their own. Human cells take folate in from the diet and do not use this pathway, which makes it a selective target: the drugs harm bacteria far more than the patient. Trimethoprim also binds the bacterial version of its target enzyme, dihydrofolate reductase, far more tightly than the human version.
Folate is turned into tetrahydrofolate, which carries single carbon atoms. Cells need those carbon atoms to make thymidine (a building block of DNA) and the purines (adenine and guanine). Without enough tetrahydrofolate the bacteria cannot make DNA, so their growth stops.
Sulphonamides such as sulfamethoxazole mimic para-aminobenzoic acid (PABA, one of the raw materials bacteria use to make folate), so they occupy its place on dihydropteroate synthase and block that early step. Trimethoprim blocks dihydrofolate reductase (DHFR), a later enzyme that converts dihydrofolate into tetrahydrofolate.
Blocking two consecutive steps of one pathway is called sequential blockade. The pair in co-trimoxazole (sulfamethoxazole plus trimethoprim) is synergistic: the combined effect exceeds the sum of the individual drug effects. A sulphonamide alone is bacteriostatic (it halts growth), whereas the combination is often bactericidal (it kills).
Key facts
- Sulphonamides
- mimic para-aminobenzoic acid and block dihydropteroate synthase, the early enzyme.
- Trimethoprim
- blocks dihydrofolate reductase, the later enzyme that makes tetrahydrofolate.
- Why bacteria are vulnerable
- they must make their own folate, whereas human cells take it in from the diet.
- Co-trimoxazole
- sulfamethoxazole plus trimethoprim, blocking two consecutive steps, and often bactericidal.
- Effect on DNA building blocks
- thymidine monophosphate, a nucleotide that DNA replication needs, falls when folate is short, and so does purine supply.
- Use
- co-trimoxazole is used for Pneumocystis jirovecii pneumonia, which is caused by a fungus rather than a bacterium.
- Caution
- trimethoprim can cause hyperkalaemia, a raised blood potassium.
Exam traps
- Blocking dihydropteroate synthase is the action of the sulphonamides, not of trimethoprim: that enzyme works earlier in the same folate pathway, while trimethoprim blocks the later enzyme dihydrofolate reductase.
- Dihydrofolate reductase is not the enzyme that sulphonamides block. It sits later in the same folate pathway and is the target of trimethoprim, which is why co-trimoxazole blocks both steps.
- The two drugs in co-trimoxazole do not both hit dihydrofolate reductase. Only trimethoprim blocks that enzyme, sulfamethoxazole blocks an earlier one, and the combination works because the two blocks are in sequence.
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