Inhibitors of folate metabolism Flashcards
What do bacteria use folate for?
DNA synthesis
Why is dihydropteroate synthetase a good antibacterial drug target?
as we don’t have this enzyme
In which 2 ways can you inhibit folate metabolism in bacteria?
- target dihydropteroate synthetase
- target dihydrofolate reductase
(both inhibit production of tetrahydrofolate (last step)
What is Prontosil and what is it used to treat?
pro-drug for sulphanilamide
- used to treat staphylococcal septicaemia
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 ppl)
What should sulphanilamide mimic?
PABA
What is the pKa of PABA compared to sulphanilamide?
PABA: 5
sulphanilamide: 10
so sulphanilamide needs to be made more acidic in order to be like PABA
What is the optimum pKa for anti-bacterial activity of a substituted sulphanilamide?
6-7
which is the only part of a substituted sulphanilamide that can be varied?
the R group, (N must be secondary and there must be a para sub aromatic ring with a para sub NH2
Which substituted sulphanilamide cured Churchill of pneumonia?
sulfapyridine
What are the other 4 main substituted sulphanilamides?
sulfapyridine
sulfadimidine
sulfadiazine (treats toxoplasmosis)
sulfamethoxazole (used for UTIs)
What does tetrahydrofolate break down into (that bacteria use)?
- thymidines
- purines
- methionine
What do we make dihydrofolate from, compared to bacteria?
we make it from folate, bacteria make it from pteridine
What does trimethoprim inhibit?
dihydrofolate reductase
why does trimethoprim not inhibit human DHFR?
due to selective toxicity - it has 50,000 x greater affinity for bacterial DHFR
what 2 things is trimethoprim used to treat?
anti-malarial (UTIs also)
Which drugs is ‘septrin’ a combination of?
sulfamethoxazole and trimethoprim
the drug Pyrimethamine is another DHFR inhibitor, which part of its structure is for DHFR activity?
Pyrimidine ring
which is more hydrophobic, trimethoprim or pyrimethamine?
Pyrimethamine - due to the chlorophenyl ring
What part of methotrexate controls DHFR activity?
pteridine ring
what is the main difference between Pyrimethamine and methotrexate?
Methotrexate targets mammalian DHFR (too polar logP -1.85, to be active in bacteria) whereas Pyrimethamine targets bacterial DHFR
What is methotrexate used for?
anti-cancer and at low doses, rheumatoid arthritis and IBS
also used to terminate pregnancies, esp ectopic
What needs to be taken if a patient is on methotrexate?
folic acid supplements (as the body will stop producing folate)
What drug cannot be taken with methotrexate?
penicillin, as it prevents elimination of methotrexate