Trimethoprim interaction with dihydrofolate

Drugs that may interact with folic acid include aminosalicylic acid, oral contraceptives, dihydrofolate reductase inhibitors (eg, methotrexate, trimethoprim), sulfasalazine, hydantoins. 

A drug receptor is a specialized target macromolecule, present on the cell surface or intracellularly, that binds a drug and mediates its pharmacologic actions. Drugs may interact with enzymes (for example, inhibition of dihydrofolate reductase by trimethoprim, p. 294),... 

W discuss three examples of "drug target" interactions (l)biotin-avidin (2) dihydrofolate reductase-trimethoprim, and (3)DNA-in-tercalator. The first is the strongest characterized protein-ligand association, the second a prototype enzyme-inhibitor interaction, and the third describes drugs interacting with nucleic acids. 

Trimethoprim sulfate/polymyxin B sulfate is an antibiotic combination. Trimethoprim blocks production of tetrahy-drofoUc acid by inhibiting the enzyme dihydrofolate reductase. Polymyxin B interacts with phospholipid components of bacterial cell membranes, increasing cell-wall permeability. They are indicated in the treatment of surface ocular bacterial infections, including acute bacterial conjunctivitis and blepharoconjunctivitis caused by susceptible organisms. 

Supra-additive interactions and potentiation appear to be much less common than antagonism and the simple additive interactions described above. Supra-additive (synergistic) interaction is said to occur if the result of interaction is greater than the sum of the drugs used alone the best example is the therapeutic synergism of certain antibiotic combinations such as sulfonamides and dihydrofolic acid reductase inhibitors such as trimethoprim. Potentiation is said to occur when a drug s effect is increased by another agent that has no such effect. The best example of this type of interaction is the therapeutic interaction of beta-lactamase inhibitors such as clavulanic acid with lactamase-susceptible penicillins. 

Figure 52 Interaction potential of an amino group with the active site of Escherichia coli dihydrofolate reductase, calculated by GRID the water molecule H39 is treated as a structural part of the enzyme in the calculations. The energy contours are plotted at — 63 kj mol they indicate two sites of strong attraction. The position of trimethoprim relative to the active site was adjusted so that the amino nitrogens N2 and N4 are located in these regions (reproduced from Figure 8 of ref. [33] with permission from the American Chemical Society, Washington. DC, USA).

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