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Chapter 26 : Compounds That Interfere with Tetrahydrofolic Acid Biosynthesis
Two groups of compounds, the sulfonamides and the 2,4-diaminopyrimidines, e.g., trimethoprim (TMP), interfere with the biosynthesis of tetrahydrofolic acid (THF). Their chemistry and development are treated separately, but their mechanism of action relies on the inhibition of two different enzymes, dihydropteroate synthetase (DHPS) and dihydrofolate reductase (DHFR), which are active in the bacterial biosynthesis of THF. Sulfonamides derived from p-aminobenzenesulfonamide are commonly referred to as sulfa drugs. Sulfonamides are synthetic antibacterial agents with an illustrious history. Chemically, the clinically useful sulfonamides are derived from paminobenzenesulfonamide. The enzyme DHPS catalyzes the displacement of pyrophosphate from the pteridine substrate. It is well established that the sulfonamides mimic p-aminobenzoic acid (PABA), which is the natural substrate required for the biosynthesis of THF. Since it does not enter bacterial cells, bacteria must synthesize dihydrofolic acid (DHF) and THF intracellularly de novo. This difference in the biochemistry of the bacterial cell and the human cell is the basis of the selective toxicity of the sulfonamides. Huovinen indicated that it may be difficult to separate the influences of the transport-related mechanisms on resistance levels. P. aeruginosa has these types of resistance mechanisms, which explains why the potency of TMP and the sulfonamides against P. aeruginosa is limited, with MICs typically in the resistant range. For certain pathogens, TMP-Sulfamethoxazole (SMX) is considered the agent of choice. These include Moraxella catarrhalis, Haemophilus influenzae causing upper respiratory infections and bronchitis, Y. enterocolitica, Aeromonas spp., Burkholderia cepacia, S. maltophilia, and Nocardia spp.