Lecture 1 - Sulfa Drugs Flashcards
1
Q
What is the gram test and what does it tell us?
A
- Divides bacteria into positive and negative.
- Crystal violet is mixed with bacteria, sticks to their membranes and stains them.
- Positive bacteria are stained purple, indicates one cell membrane is present with a thick peptidoglycan cell wall.
- Negative bacteria are stained red, indicates two cell membranes are present with a thin peptidoglycan cell wall.
2
Q
Draw the structure of a sulfonamide and annotate.
A
Essential:
- Aromatic ring
- Para-amino primary amine
- Sulfa group
R’ is the only position that can be changed
3
Q
What was the first sulfonamide drug and how does it operate?
A
- Prontosil
- Was originally developed as an azo dye
- Is an example of a prodrug, gets reduced in-vivo to its active metabolite sulfanilamide
- Sulfonamides are biologically inactive
4
Q
How are sulfonamides reduced in the body?
A
*see notes*
5
Q
How can we improve the activity of sulfonamides?
A
- Sulfonamides are poorly water soluble and toxic through crystallisation in the kidney
- Second generation drug sulfadiazine has improved solubility through increased polarity
- Injected to avoid the acidic stomach environment
6
Q
What is the site of action for sulfa drugs?
A
- Target enzyme is dihydroptetrate synthase, involved in the biosynthesis of folic acid.
- Folic acid is essential for the transport of 1-C units in the biosynthesis of DNA.
- This pathway is only found in bacterial cells.
- Without tetrahydrofolic acid, DNA cannot be synthesised preventing the replication of bacterial cells without harming eukaryotic cell processes.
7
Q
Draw the mechanism for the biosynthesis of folic acid.
A
8
Q
How does sulfanilamide act as a competitive inhibitor?
A
- Sulfanilamide competes with PABA for the active site of dihydropterate synthase, making it a reversible competitive inhibitor.
- E + I ⇔ E.I → E.P X
- A good inhibitor has a greater substrate dissociation rate (KM) than inhibitor dissociation rate (Ki).
9
Q
What is the structure and function of DHFR? Which drug is its competitive inhibitor?
A
- Trimethoprin is a competitive inhibitor of DHFR that works as an anti-bacterial and anti-malarial agent.
- Bacterial DHFR structurally very different to human DHFR.
- Is the second enzyme in the biosynthesis of folic acid.
10
Q
What is septrin and what is it an example of?
A
- Septrin is a synergistic mixture of trimethoprin and sulfamethoxazole, combined to counteract resistance + give a greater combined effect.
- These drugs are examples of antimetabolites (compounds that block enzymes involved in metabolic pathways) and bacteriostatic drugs (compounds that inhibit growth + replication but dont directly kill).
11
Q
Draw the structure of sulfamethoxazole.
A
