Trimethoprim selective bacterial DHFR inhibition

Trimethoprim should not be used in combination with pyrimethamine since both drugs are DHFR inhibitors, although pyrimethamine is more selective for the protozoal enzyme and trimethoprim for the bacterial enzyme. When used together, trimethoprim competitively inhibits pyrimethamine, thus decreasing the efficacy of this more effective compound. In addition, pyrimethamine and trimethoprim have at least... 

A most interesting and useful development concerning DHR inhibitors was the selectivity of inhibition observed between different classes of compounds against dihydrofolate reductases from mammals, protozoa and bacteria, which was found to be due to marked differences in binding affinity to the enzyme methotrexate binds very tightly to all reductases tested and is lethal to any cell it can enter, while trimethoprim and pyrimethamine have selectively strong affinity for bacterial and plasmodial reductases, respectively. This helped to rationalise the clinical use of DHFR inhibitors alone or in combination with sulphonamides and sulphones while trimethoprim is used mainly for bacterial infections, pyrimethamine is used for protozoal infections [58a]. 

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