INHIBITORS OF FOLATE METABOLISM Flashcards
What do bacteria use folate for?
DNA synthesis
How does folate metabolism differ in humans vs bacteria?
- Humans - consume folate and it is converted to tetrahydrofolate
- Bacteria - synthesise the precursor (dihydropteroare diphosphate + p-aminobenzoic acid (PABA)) and using 2 enzymes, this is converted to tetrahydrofolate
- Bacteria uses dihydropteroate synthase - humans don’t have this enzyme
How is folate metabolism in humans vs bacteria similar?
Humans and bacteria both utilis dihydrofolate reductase
What is dihydrofolate reductase?
An enzyme used in the final stage to make tetrahydrofolate
What is tetrahydrofolate for?
- Tetrahydrofolate is essential for C1 metabolism.
- It is converted to 5,10-methylenetetra-hydrofolate, which is involved in DNA synthesis
Why is the enzyme dihydropteroate synthetase a good antibacterial drug target?
Because humans don’t have this enzyme
What does dihydropteroate synthetase do in (and only in) bacteria?
Catalyzes the combination of dihydropteroare diphosphate + p-aminobenzoic acid (PABA)
What is the pka of para-aminobenzoic acid?
pKa 5
pKa is the pH at which 50% is ionised.
Prontosil was shown to be a prodrug for which drug?
Sulfanilamide
How was sulphanilamide made less foul tasting?
An elixir was produced, using diethylene glycol as a solvent (but it was this solvent that killed 107 people)
- Frances Kelsey roved the deaths were due to diethylene glycol
Why is diethylene glycol toxic?
Because the liver oxidises the hydroxyl groups to toxic aldehydes
How does sulphanilamide work and what are its limitations?
Mimics para-aminobenzoic acid
- PABA is converted by dihydropteroate synthetase = no tetrahydrofolate made
What are the limitations of sulfanilamides?
- PABA: 5
- sulphanilamide: 10
- Difference in pKa means ionisation isn’t ideal and reduces its potential as a drug (sulphanilamide needs to be more acidic)
What is the optimum pKa (acidic) of the sulfonamide group for bacterial activity?
pKa = 6-7
How can sulfanilamides be made more acidic?
The R-group is the only molecule that can be changed
- N must be secondary
- Aromatic ring must be para-substituted with a para-amino group (NH2)
What are substituted-sulphanilamides used for?
Treating gram-positive bacterial infections e.g. pneumococci and meningococci
What are the 4 main substituted sulphanilamides?
- sulfapyridine
- sulfadimidine
- sulfadiazine
- sulfamethoxazole
What is sulfadiazine used to treat?
Toxoplasmosis
Describe the pathway of tetrahydrofolate biosynthesis in bacterial cells, including the enzymes in evolved in each step
What does tetrahydrofolate break down into (that bacteria use)? (3)
- thymidines
- purines
- methionine
What does trimethoprim inhibit?
Dihydrofolate reductase
Why is trimethoprim selectively toxic?
Because its affinity for dihydrofolate reductase in bacteria is 50,000x stronger than for human dihydrofolate reductase
Co-trimoxazole is a combination of which two medicines?
Trimethoprim
Sulphamethoxazole
What is pyrimethamine?
Pyrimethamine is another dihydrofolate reducatse inhibitor.
