Folic acid/folate bacterial synthesis

Both the sulfonamides and trimethoprim interfere with bacterial folate metabolism. For purine synthesis tetrahydrofolate is required. It is also a cofactor for the methylation of various amino acids. The formation of dihydrofolate from para-aminobenzoic acid (PABA) is catalyzed by dihydropteroate synthetase. Dihydrofolate is further reduced to tetrahydrofolate by dihydrofolate reductase. Micro organisms require extracellular PABA to form folic acid. Sulfonamides are analogues of PABA. They can enter into the synthesis of folic acid and take the place of PABA. They then competitively inhibit dihydrofolate synthetase resulting in an accumulation of PABA and deficient tetrahydrofolate formation. On the other hand trimethoprim inhibits dihydrofolate... 

Several antibacterial drugs inhibit bacterial nucleic acid synthesis by inhibiting the production of folic acid.17 Folic acid serves as an enzymatic cofactor in a number of reactions, including synthesis of bacterial nucleic acids and certain essential amino acids. The pathway for synthesis of these folic acid cofactors is illustrated in Figure 33-2. Certain antibacterial drugs block specific steps in the folate pathway, thus impairing the production of this enzymatic cofactor and ultimately impairing the production of nucleic acids and... 

Mammalian cells (and some bacteria) lack the enzymes required for folate synthesis and depend upon exogenous sources of folate therefore, they are not susceptible to sulfonamides. Sulfonamide resistance may occur as a result of mutations that cause overproduction of PABA, cause production of a folic acid-synthesizing enzyme that has low affinity for sulfonamides, or cause a loss of permeability to the sulfonamide. Dihydropteroate synthase with low sulfonamide affinity is often encoded on a plasmid that is transmissible and can disseminate rapidly and widely. Sulfonamide-resistant cells may be present in susceptible bacterial populations and can emerge under selective pressure. 

Tetrahydrofolic acid (THF) is a coenzyme in the synthesis of purine bases and thymidine. These are constituents of DNA and RNA and are required for cell growth and replication. Lack of THF leads to inhibition of cell proliferation. Formation of THF from dihydrofolate (DHF) is catalyzed by the enzyme dihydrofolate reductase. DHF is made from folic acid, a vitamin that cannot be synthesized in the body but must be taken up from exogenous sources. Most bacteria do not have a requirement for folate, because they are capable of synthesizing it-more precisely DHF-ffom precursors. Selective interference with bacterial biosynthesis of THF can be achieved with sulfonamides and trimethoprim. 

Trimethoprim inhibits another enzyme, dihydrofolate reductase, in the same folic acid metabolic pathway. Folic acid is converted into folate, which then has to be converted into an activated form by dihydrofolate reductase. In this way, trimethoprim interferes with the conversion of folate into its activated form, which is a cofactor in the synthesis of bacterial DNA. Dihydrofolate reductase also occurs in host cells, but it is less sensitive to trimethoprim. Trimethoprim is used to treat urinary tract infections. It is also formulated in combination with a sulphonamide, when it is known as co-trimoxazole, to treat pneumonia in patients with HIV (see page 170). Due to the synergistic effect of the two drugs, this combination is more effective than either drug alone. 

Following the introduction of the sulphonamides in clinical use, the antibacterial activity was found to be inhibited by the presence of pus. This inhibitory effect of pus was found to be due to the presence of the stmcturally similar p-aminobenzoic acid (PABA) a compound which is also present in folic acid. This led to the observation that the sulphonamides competed with PABA, leading to the dismption of folate synthesis and cessation of bacterial growth. The importance of the sulphonamides in... 

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