FP - Folate Synthesis Inhibitors

Question 1

What is selective toxicity and what can it be (4)?

Answer 1

Using drugs to kill an invading species without damage to the host

Can be:

• Anticancer
• Antiviral
• Antiprotozoal
• Antibacterial

Question 2

Differentiate between selective toxicity and disinfectants/sterilizing agents

Answer 2

Selective toxicity targets specific mechanisms in pathogens, whereas disinfectants/sterilizing agents kill everything

Question 3

What are antibiotics, and where do they primarily come from?

Answer 3

Mostly natural products; agents produced by microorganisms to kill other microorganisms

Question 4

Describe the history of antibiotics

Answer 4

Pasteur initially came up with the concept of antibiotics

Lister realised if he disinfected all equipment, it would remove bacteria (less complications)

Koch realised atoxyl was making people blind (very toxic)

Ehrlich sythesised other derivatives of molecule making it less toxic

Question 5

Name the first synthetic compound used as an antibiotic and its effectiveness

Answer 5

Atoxyl; a synthetic compound that was very effective

Question 6

Describe Paul Ehrlich’s concepts (3)

Answer 6

1) Drugs could be metabolically activated

2) Do not need to actually kill the bacteria

• Some antibiotics kill bacteria: Bactericidal
• Some antibiotics do not kill bacteria: Bacteriostatic
  Inhibit their growth and stop further growth

3) Structure-Activity Relationship (S.A.R.)

Arsphenamine was the first organic compound for treating syphilis (1909)

Question 7

What was the first organic compound for treating syphilis?

Answer 7

Arsphenamine

Question 8

What was the first sulfonamide antibacterial, and what is its mechanism of action?

Answer 8

Prontosil was the first sulfonamide antibacterial

• Inactive in vitro and cleaved down in vivo

Question 9

Structure of sulfonamides (3)

Answer 9

Amino terminus cannot be changed or modified

Benzene ring more active than other aromatics

Sulphonamide end can have other groups attached

Question 10

Explain the mechanism of action of sulfonamides in bacteria

Answer 10

Sulfonamides compete with pAB, generating a false product that cannot be used for the next reaction in the synthesis of folate, leading to the pathway’s interruption

Question 11

Why is folic acid important?

Answer 11

1 Carbon metabolism:
Tetrahydrofolate is a carbon donor

Providing 1C units (methyl groups) for the synthesis of purines, amino acids, and other important cell components

Question 12

Why do folate synthesis inhibitors not affect humans?

Answer 12

We do not synthesise our own folate

Question 13

Why do sulfonamides work so well? (3)

Answer 13

1) They generate a false product (exhausting the supply of the pteridine precursor)

• so compounds before the block do not build up and compete.

2) Bacteria have no uptake mechanisms for the product.

3) We do not synthesise folate – though it is an essential part of our diet. pAB is not present in our cells.

Question 14

How has resistance decreased the use of sulfonamides (4)?

Answer 14

They are less widely used as a result of resistance due to:

• increased pAB level
• increased uptake of folate
• reduced drug uptake
• drug metabolism

Question 15

What are the specific medical applications of sulfonamides?

Answer 15

Used to treat

• urinary tract infections
• meningitis
• veterinary medicine

Broad spectrum antibacterials – affecting both Gram +ve and Gram –ve bacteria

Question 16

What is the primary use of trimethoprim, and how does it complement sulfonamides?

Answer 16

It targets the last part of the folate synthesis pathway, and when administered with sulfonamides, inhibits two points in the same pathway

Question 17

Is trimethoprim more effective in humans or bacteria?

Answer 17

Targets something that exists in both but has a much higher affinity for the folate in bacteria than in humans