Coenzyme Reaction

N10-Formyl-FAH4 Met-tRNA -Formyl-Met-tRNA

N5N10=Methylene-FAH4 Glycine _^ Serine

N5-Formyl-FAH2 Homocysteine ->- Methionine

Figure 6.9 • The thymidylate synthetase reaction and other reactions representing the one-carbon pool.

Reaction Release Trimethoprim
Figure 6.10 # Folate pathways in humans and bacteria and the sites of inhibition by sulfonamides and trimethoprim. (continues on next page)

high affinity for the malaria protozoan's folate reductase, but it does have a high affinity for bacterial folate reductase.

The reverse situation exists for the antimalarial drug pyrimethamine.112 Trimethoprim does have some affinity for human folate reductase, and this is the cause of some of the toxic effects of the drug.

Spectrum of Action of the Sulfonamides

Sulfonamides inhibit Gram-positive and Gram-negative bacteria, nocardia, Chlamydia trachomatis, and some protozoa. Some enteric bacteria, such as e. coli and Klebsiella, Salmonella, Shigella, and Enterobacter spp. are inhibited. Sulfonamides are infrequently used as single agents. Once drugs of choice for infections such as PCP, toxoplasmosis, nocardiosis, and other bacterial infections, they have been largely replaced by the fixed drug combination TMP-SMX and many other antimicrobials. Many strains of once-susceptible species, including meningococci, pneumococci, streptococci, staphy-lococci, and gonococci are now resistant. Sulfonamides are, however, useful in some urinary tract infections because of their high excretion fraction through the kidneys.

Ionization of Sulfonamides

The sulfonamide group, SO2NH2, tends to gain stability if it loses a proton, because the resulting negative charge is resonance stabilized.

Since the proton-donating form of the functional group is not charged, we can characterize it as an HA acid, along with carboxyl groups, phenols, and thiols. The loss of a proton can be associated with a pKa for all of the compounds in the series. For example, the pKa of sulfisoxazole (pKa 5.0) indicates that the sulfonamide is a slightly weaker acid than acetic acid (pKa 4.8).

NH Dihydrofolic Acid (FAH2) 0

NH Dihydrofolic Acid (FAH2) 0

Folate Reductase Trimethoprim

Sar Trimethoprim And Sulphonamides

Folic Acid (diet); FA

Folate Reductase Trimethoprim

Tetrahydrofolic Acid (FAH4;

Folic Acid (diet); FA

Tetrahydrofolic Acid (FAH4;

Sar Trimethoprim And Sulphonamides
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