Antibacterials

What are some differences between gram positive and gram negative bacteria?

• Gram-positive bacteria:

  • Thick peptidoglycan layer

  • Contains acids

• Gram-negative bacteria:

  • Thin peptidoglycan layer

  • Two cell membranes

  • Outer membrane with lipopolysaccharides

  • More resistant to antibiotics than gram-positive bacteria

How to test for gram negative/positive bacteria

the Gram Test

• heteraromatic purple stain (yrstal violet) sticks to the outer membrane

• decolourise with an organic solvent

• -ve cells are red/pink (E. coli)

• +ve cells are purple

Describe the appearance of:

1. Staphylococcus aureus

2. Streptococcus sp.

3. E. coli

1. round clusters of cells

2. chains

3. isolated round cells

What was dangerous about the first antibacterial agents?

Contained arsenic which could easily lead to poisoning

What is an example of a Sulfonamide and how do they work?

The prodrug prontosil

In the body, it turns into sulfanilamide, the active antibacterial compound.

It inhibits enzymes essential for bacteria growth

What is a prodrug

A compound that is metabolised in vivo into the active form of the drug

e.g. protosol is reduced to sulfonamide

How can you improve the Structure-Activity Relationship (SAR) in a drug

Can only modify non-essential parts of the drug

R group can be replaced to create a drug that is more water-soluble, or causes less kidney damage

What is the site of action of sulfonamide drugs?

Inhibit the enzyme dihydropterate synthetase, which helps synthesise folic acid in bacteria.

Folic acid is used for DNA synthesis in bacteria so without it they die.

Describe the biosynthesis of folic acid

• dihydropterate synthase catalyses SN2 reaction 

• diphosphate group is a good leaving group

• DHFR (anti-microbial dihydrofolate reductase) reduces imine bonds using NADH (nature's NaBH4)

What type of inhibitors are sulfa drugs

reversible competitive inhibitors (binds to active site of dihydropterate synthase)

What is DHFR

Dihydrofolate reductase

Acts as a reducing agent in the bacterial folic acid synthesis pathway (nature’s NaBH4)

What is a drug that inhibits DHFR

Trimethorpin - antibacterial agent

What is Septrin

Mixture of Trimethoprin and sulfamethoxazole which counteracts resistance to one of the drugs.

The sum of the two drugs together is more powerful than the effect of the two separately

What are Trimethoprin and sulfamethoxazole examples of

• Anti-metabolites - compounds that block metabolic enzymes

• Bacteriostatic drugs - compounds that inhibit growth and replication, not kill directly