Tetrahydrofolate synthesis inhibitors

(Catherine)

Ingestion of prontosil (azo dye)formed what antibiotic?

Sulfonamides

What structures in a sulfonamide are critical for heir antibacterial activity?

- S linked to a benzene ring
- Amino group linked to the same benzene ring in para position

Describe the antimicrobial activity of sulfonamides

- Bacteriostatic
- Active against Gram + and Gram - bacteria (broad spectrum)
- Resistance is very common

In bacteria, what molecule is necessary for purine synthesis and 1C-transfer reactions?

Tetrahydrofolic acid

How do humans/animals obtain tetrahydrofolic acid?

- Take up folic acid (B9) from diet or gut bacteria
- Folic acid gets reduced to dihydrofolic acid then tetrahydrofolic acid

What does dihydropteroate synthase do?

Converts pteridine & para-aminobenzoic acid (PABA) into dihydropteroic acid

MOA of sulfonamides

- Mimics & competes with dihydropteroate synthase to inhibit dihydropteroic acid synthesis

Why don't sulfonamides affect human cells?

Human cells don't synthesize tetrahydrofolic acid using dihydropteroate synthase

Mechanisms of resistance for sulfonamides

- Mutate dihydropteroate synthase to decrease affinity for sulfonamides
- Decrease permeability of cell envelope
- Active efflux of the drug
- Increased production of PABA
- Relying on an alternative metabolic pathway for tetrahydrofolate synthesis

ADRs of sulfonamides

Crystalluria

What is crystalluria?

Formation of crystals by acetylated forms of sulfonamides in the urinary tract

MOA of trimethoprim

Inhibits reduction of dihydrofolic acid to tetrahydrofolic acid by DHFR

Why does Trimethoprim not affect human cells?

Bacterial DHFR is different from human DHFR

Why is trimethoprim administered with sulfonamides?

Due to combined synergism - trimethoprim inhibits same metabolic pathway of sulfonamides

What does it mean if there is a synergistic effect between two drugs?

Less than 50% of each drug is needed to get the effect of 100% of each individual drug

What is the ideal activity/plasma ratio of trimethoprim + sulfamethoxazole?

1/20

Which drug in Bactrim is more lipophilic with a larger Vd?

Trimethoprim

In order for the drugs in Bactrim to obtain their ideal ratio at peak plasma concentrations, what is the ideal oral ratio?

1/5 of trimethoprim:sulfa

Resistance to Bactrim is (more/less) likely than resistance to each single drug

Less