26 - clavulinic acid Flashcards
what are cephalosporins, when were they discovered and where
- Discovered 1948
- Fungus growing in an Italian sewer
- structure related to penicillin: beta-lactam, carboxylic acid, side chain
- blocks the action of transpeptidase by forming a covalent bond with the transpeptidase
what are the advantages to Cephalosporin
- Lipophilic – broad spectrum
- can kill gram positive and gram negative
- [4,6] ring system less reactive than [4,5]
- Activity against resistant strains
- more difficult to open up the ring
- Less risk of allergy
- less change of having random Nu react with it
- Activity against resistant strains
what are the disadvantages of Cephalosporins
- Not orally active
- sensitive to acid, will react with it in the same way penicillin does
- Low potency (larger doses)
- need semi-synthesis to improve properties
what will semisynthesis turn Cephalosporin into
couple of chemical reactions and you get intermediate 7-ACA
what are two properties you can modify on 7-ACA and what will each improve
- add side chain = protect against acid
- attach a piece at OH = improve bioavailibility
what is clavulanic acid, when was it discovered, and what does it target
- Discovered in 1976
- Streptomyces clavuligerus
- Not an antibiotic
- Does not inhibit transpeptidase
- Does not kill bacteria
- the target of this material is β-lactamase, thats why its so important
how does clavulanic acid destroy β-lactamase
- Clavulanic acid reacts with β-lactamase to make a non-functional version of β-lactamase
- destroys the resistance mechanism and allows you to use the antibiotic
how is clavulinic acid used clinically
- Inhibits β-lactamase
- “protects” the antibiotic from the resistance enzyme
- mix with the anti-biotic
how is β-lactam antibiotic used clinically
- Inhibits transpeptidase
- Kills bacteria
explain the selectivity of clavulinic acid with respect to β-Lactamase and transpeptidase
- β-Lactamase: Clavulinic acid easily fits into the pocket of β-Lactamase
transpeptidase: Clavulinic acid does not fit inside the big pocket, not enough intermolecular forces and too many water molecules. not able to hold the Clavulinic acid in place.
what is the most common type of drug-drug interaction
One drug changes the bioavailability of another. either amplifies or reduces the amount of activity
how does grapefruit inhibit liver function and why can it cause a toxicity issue
- Bergamotin is found in grapefruit
- Metabolized by liver
- Metabolite irreversibly binds a glutamine on CYP450
- CYP450 is deactivated
- if you are taking a drug and eat grapefruit = toxicity issue
- you get an overdose of the drug because the liver function is deactivated, so dosage of the drug that enters the body is much higher than intended
what is vancomycin and when was it discovered, what is it composition
- Glycopeptide drug
- Sugars (glycol)
- Short protein (peptide) containing 7 amino acids
- chemically modified amino acids + sugars
- Aromatic rings on peptide are linked forming a bowl-shaped structure
- discovered in 1956 (Streptomyces orientalis (bacteria))
how does vancomycin prevent cell wall cross linking
- vancomycin has many amino acid backbones connected by cross-links = important 3D structure
- Vancomycin Binds very strongly to D-Ala-D-Ala tail of peptide chains
- Prevents transpeptidase from binding
- bowls of Vancomycin are right size to cover D-Ala-D-Ala = no transpeptidase cross link
what kind of inhibition does vancomycin employ when it prevents cross linking
- Competitive
- When the inhibitor is bound to the substrate, the enzyme cannot interact with the substrate
- Enzyme function is blocked
