Trimethoprim interaction with enzymes

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. 

Not established. The pharmaeokinetie and pharmacodynamic evidence in-dieates that eo-trimoxazole is not likely to reduce the effectiveness of combined oral eontraeeptives. Although there are a number of reports of contraceptive failure attributed to co-trimoxazole, these are anecdotal and unconfirmed, whereas the studies suggest increased contraceptive efficacy (but see below). It is possible that the cases are coincidental, and fit within the normal failure rate of combined oral contraceptives. The UK Family Planning Authority considered that it was almost certain that co-trimoxazole and sulphonamides did not interact with combined oral contraceptives. However, the Faculty of Family Planning and Reproductive Health Care (FFPRHC) Clinical Effectiveness Unit has issued guidance on the use of antibacterials with hormonal contraceptives. Although they recognise that there is poor evidence for contraceptive failure, they recommend that additional contraceptives, such as condoms, should be used for short courses of antibacterials, see Hormonal contraceptives + Antibacterials Penicillins , p.981, for more detailed information. This applies to both the oral and the patch form of the combined contraceptive. This advice has usually been applied to only broad-spectrum antibacterials that do not induce liver enzymes but the FFPRHC notes that some confusion has occurred over which antibacterials are considered to be broad-spectrum , and thus they recommend that this advice is applied to all antibacterials that do not induce liver enzymes, which would include co-trimoxazole, sulfonamides and trimethoprim. ... 

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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