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# Sulfonamides and trimethoprim

Antifolates that starve bacteria of folate in two steps: sulfonamides block dihydropteroate synthase, trimethoprim blocks dihydrofolate reductase.

Updated 2026-11-01

## What they are

The oldest synthetic antibacterials and their partner trimethoprim. Bacteria must make their own folate, while human cells take it from the diet, which is the basis of their selectivity. The pair sulfamethoxazole–trimethoprim (co-trimoxazole) is the most used member.

## Mechanism of action

Sulfonamides look like para-aminobenzoic acid (PABA) and compete with it at dihydropteroate synthase, so less dihydrofolate is made. Trimethoprim inhibits bacterial dihydrofolate reductase, the next step to tetrahydrofolate. Without tetrahydrofolate the bacterium cannot build thymidine and purines; blocking two consecutive steps makes the combination bactericidal and slows resistance.

Target: Dihydropteroate synthase (sulfonamides) and dihydrofolate reductase (trimethoprim)

## Key points

- Severe skin reactions (Stevens–Johnson syndrome, toxic epidermal necrolysis) are a classic sulfonamide risk.
- Trimethoprim behaves like amiloride in the distal nephron: it can raise potassium and the serum creatinine.
- Kernicterus risk: sulfonamides displace bilirubin, so they are avoided in neonates and at the end of pregnancy.
- Crystalluria: good fluid intake keeps the drug dissolved in urine.
- Haemolysis in G6PD deficiency; folate-deficiency megaloblastic anaemia is a contraindication.

## Drugs in this class

- [**Sulfamethoxazole + trimethoprim (co-trimoxazole)** Two antifolates in one tablet. Key for preventing and treating Pneumocystis, for urinary infections, toxoplasmosis and… Dihydropteroate synthase (sulfamethoxazole) and dihydrofolate reductase (trimethoprim)](https://durgical.com/en/pharmacology/sulfamethoxazole-trimethoprim/)
- [**Sulfadiazine** A sulfonamide that reaches the brain well; with pyrimethamine it is the classic treatment of toxoplasmosis, including… Dihydropteroate synthase (bacterial and Toxoplasma folate pathway)](https://durgical.com/en/pharmacology/sulfadiazine/)
- [**Trimethoprim** A dihydrofolate reductase inhibitor used alone for cystitis and as the partner in co-trimoxazole. It can raise… Bacterial dihydrofolate reductase](https://durgical.com/en/pharmacology/trimethoprim/)

## Others in the class

- sulfadoxine (with pyrimethamine, antimalarial)
- sulfacetamide (eye)
- silver sulfadiazine (burns)
- dapsone (related sulfone)

## Test yourself

Think of the answer, then tap the question to see it.

## Which two consecutive enzymes does co-trimoxazole block?

Dihydropteroate synthase (sulfamethoxazole) and dihydrofolate reductase (trimethoprim).

## Why can trimethoprim cause hyperkalaemia?

It blocks the epithelial sodium channel of the distal nephron, like amiloride, so less potassium is secreted.

## Why are sulfonamides avoided in newborns?

They displace bilirubin from albumin and can cause kernicterus.

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Educational content on how drugs work; not a prescribing guide and no substitute for a health professional's advice. No doses are given.

Sources: [DailyMed - SULFAMETHOXAZOLE AND TRIMETHOPRIM tablet](https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3ef62512-0dc3-4821-9b60-6b375841c4c0) (DailyMed (U.S. National Library of Medicine), 2026); [DailyMed - SULFADIAZINE tablet](https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8993651b-fff6-4e3f-9b60-78587bc9bcee) (DailyMed (U.S. National Library of Medicine), 2026); [DailyMed - TRIMETHOPRIM tablet](https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=249e938d-f181-47c4-a082-372d65462f33) (DailyMed (U.S. National Library of Medicine), 2026); [eEML - Electronic Essential Medicines List](https://list.essentialmeds.org/?query=trimethoprim) (World Health Organization, 2025).

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Representative model, for educational purposes only.

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Source: https://durgical.com/en/pharmacology/classes/sulfonamides-and-trimethoprim/
License: CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). Cite as: DurgiPedia (durgical.com), https://durgical.com/en/pharmacology/classes/sulfonamides-and-trimethoprim/