Inhibitors of folate metabolism

Question 1

What do bacteria use folate for?

Answer 1

DNA synthesis

Question 2

Why is dihydropteroate synthetase a good antibacterial drug target?

Answer 2

as we don’t have this enzyme

Question 3

In which 2 ways can you inhibit folate metabolism in bacteria?

Answer 3

• target dihydropteroate synthetase
• target dihydrofolate reductase
  (both inhibit production of tetrahydrofolate (last step)

Question 4

What is Prontosil and what is it used to treat?

Answer 4

pro-drug for sulphanilamide

- used to treat staphylococcal septicaemia

Question 5

how was sulphanilamide made less foul tasting?

Answer 5

an elixir was produced, using diethylene glycol as a solvent (but it was this solvent that killed 107 ppl)

Question 6

What should sulphanilamide mimic?

Answer 6

PABA

Question 7

What is the pKa of PABA compared to sulphanilamide?

Answer 7

PABA: 5
sulphanilamide: 10
so sulphanilamide needs to be made more acidic in order to be like PABA

Question 8

What is the optimum pKa for anti-bacterial activity of a substituted sulphanilamide?

Answer 8

6-7

Question 9

which is the only part of a substituted sulphanilamide that can be varied?

Answer 9

the R group, (N must be secondary and there must be a para sub aromatic ring with a para sub NH2

Question 10

Which substituted sulphanilamide cured Churchill of pneumonia?

Answer 10

sulfapyridine

Question 11

What are the other 4 main substituted sulphanilamides?

Answer 11

sulfapyridine
sulfadimidine
sulfadiazine (treats toxoplasmosis)
sulfamethoxazole (used for UTIs)

Question 12

What does tetrahydrofolate break down into (that bacteria use)?

Answer 12

• thymidines
• purines
• methionine

Question 13

What do we make dihydrofolate from, compared to bacteria?

Answer 13

we make it from folate, bacteria make it from pteridine

Question 14

What does trimethoprim inhibit?

Answer 14

dihydrofolate reductase

Question 15

why does trimethoprim not inhibit human DHFR?

Answer 15

due to selective toxicity - it has 50,000 x greater affinity for bacterial DHFR

Question 16

what 2 things is trimethoprim used to treat?

Answer 16

anti-malarial (UTIs also)

Question 17

Which drugs is ‘septrin’ a combination of?

Answer 17

sulfamethoxazole and trimethoprim

Question 18

the drug Pyrimethamine is another DHFR inhibitor, which part of its structure is for DHFR activity?

Answer 18

Pyrimidine ring

Question 19

which is more hydrophobic, trimethoprim or pyrimethamine?

Answer 19

Pyrimethamine - due to the chlorophenyl ring

Question 20

What part of methotrexate controls DHFR activity?

Answer 20

pteridine ring

Question 21

what is the main difference between Pyrimethamine and methotrexate?

Answer 21

Methotrexate targets mammalian DHFR (too polar logP -1.85, to be active in bacteria) whereas Pyrimethamine targets bacterial DHFR

Question 22

What is methotrexate used for?

Answer 22

anti-cancer and at low doses, rheumatoid arthritis and IBS

also used to terminate pregnancies, esp ectopic

Question 23

What needs to be taken if a patient is on methotrexate?

Answer 23

folic acid supplements (as the body will stop producing folate)

Question 24

What drug cannot be taken with methotrexate?

Answer 24

penicillin, as it prevents elimination of methotrexate