Bacterial Resistance to Antibiotics: From Molecules to Man

Prokaryotes and unicellular eukaryotes such as yeasts or Plasmodium can synthesize folate de novo via the folic acid synthesis pathway (Figure 7.1). The steps of this pathway include:(i) the condensation of dihydropteridine pyrophosphate (DHPP) 1 with p-aminobenzoic acid (pABA) 2 by dihydropteroate synthase (DHPS, EC 2.5. 1.15) to form dihydropteroate (DHP) 3;(ii) the addition of glutamate to DHP by dihydrofolate synthase (DHFS, EC 6.3. 2.12) to form dihydrofolate (DHF) 4; and (iii) the reduction of DHF to form tetrahydrofolate (THF) 5, catalyzed by dihydrofolate reductase (DHFR, EC 1.5. 1.3)[1]. DHPS is thus an essential enzyme responsible for the de novo synthesis of the folate molecule. Tetrahydrofolate produced by this pathway is required for one carbon trans--fer reactions in the biosynthesis of a range of biomolecules, such as nucleotides and amino acids [2]. DHFR is the enzyme responsible for the maintenance of folate pools in their physiologic, reduced states. DHFR, in fact, is needed for the intracellular conver--sion of synthetic folic acid into the THF forms that can participate in folate/homocyst--eine metabolism. Reduction of DHFR enzymatic activity diminishes the THF pool inside the cells, affecting the level of folate coenzymes and thus purine and pyrimidine biosynthesis [3]. This may as well influence homocysteine levels and methylation pro--cesses, because methyl-THF is needed for the re-methylation of homocysteine to form methionine, thereby ensuring the provision of S-adenosylmethionine (SAM) necessary for most biological methylation processes [4]. In contrast to prokaryotes and