Folate Antagonists

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Folate Antagonists

PHRM 304



Overview

• Enzymes requiring folate-derivedcofactors are essential for thesynthesis of purines and pyrimidines(precursors of RNA and DNA) andother compounds necessary forcellular growth and replication.

• Therefore, in the absence of folate,cells cannot grow or divide.



Mechanism of action

Para-aminobenzoic acid (PABA) + PteridineDihydropteroate

synthetase[GTP] Sulfonamides

Competitive inhibition

Dihydropteroic acid

Dihydrofolatesynthetase

L-Glutamate

Trimethoprim

Dihydrofolic acid (folic acid)

Tetrahydrofolic acid

Dihydrofolatereductase

2 NADPH

2 NADP+

PurinesThymidine Methionine

DNA, RNA DNA t RNA, Proteins

Cofactors

Folic acid metabolism:



Overview

• To synthesize the critical folatederivative, tetrahydrofolic acid,humans must first obtain preformed

folate in the form of folic acid as avitamin from the diet.

• In contrast, many bacteria are

impermeable to folic acid and otherfolates and, therefore, must rely ontheir ability to synthesize folate de

novo.



Overview

• The sulfonamides (sulfa drugs) are afamily of antibiotics that inhibit thisde novo synthesis of folate.



Sulfonamides M/A

• In many microorganisms, dihydrofolicacid is synthesized from p-aminobenzoic acid (PABA), pteridine,

and glutamate.

• All the sulfonamides currently inclinical use are synthetic analogs of

PABA.



Sulfonamides M/A

• Because of their structural similarityto PABA, the sulfonamides competewith this substrate for the bacterial

enzyme, dihydropteroate synthetase.

• They thus inhibit the synthesis of bacterial dihydrofolic acid and,

thereby, the formation of its essentialcofactor forms.



Sulfonamide: Resistance

• Bacteria that can obtain folates fromtheir environment are naturallyresistant to these drugs.

• Acquired bacterial resistance to thesulfa drugs can arise from plasmidtransfers or random mutations.



Sulfonamide: Resistance

• Resistance is generally irreversibleand may be due to

1) An altered dihydropteroatesynthetase

2) Decreased cellular permeability tosulfa drugs, or

3) Enhanced production of the naturalsubstrate, PABA



Trimethoprim

• Trimethoprim, a potent inhibitor of bacterial dihydrofolate reductase,exhibits an antibacterial spectrum

similar to that of the sulfonamides.

• Trimethoprim is most oftencompounded with sulfamethoxazole,

producing the combination calledcotrimoxazole.



Trimethoprim M/A

• The active form of folate is thetetrahydro-derivative that is formedthrough reduction of dihydrofolic acid

by dihydrofolate reductase.

• This enzymatic reaction is inhibitedby trimethoprim, leading to a

decreased availability of thetetrahydrofolate coenzymes requiredfor purine, pyrimidine, and amino

acid synthesis.



Trimethoprim M/A

• The bacterial reductase has a muchstronger affinity for trimethoprimthan does the mammalian enzyme,

which accounts for the drug'sselective toxicity.



FigureSynergism betweentrimethoprim and

sulfamethoxazoleon the inhibition of growth of Escherichia coli.



Adverse effects

• Trimethoprim can produce theeffects of folic acid deficiency.

• These effects include megaloblasticanemia, leukopenia, andgranulocytopenia, especially inpregnant patients and those having

very poor diets.

• These blood disorders can bereversed by the simultaneous

administration of folinic acid, which

Folate Antagonists

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