25 - penicillin design ii Flashcards
describe how penicillin G is turned into artificial penicillin. why can you not just add an NH2
- start with mold juice → purified into penicillin G
- semi-syntheses = synthesis starting with something naturally occurring
- using amidase to cut off left side of penicillin G → 6-APA → coupling reaction to attach a new left side group (Attach acyl group to NH2 of 6-APA)
- there is no chemical reaction that will only add the NH2 reaction to penicillin G
what is DCC and what does it do
peptide coupling reagent, invented for work in penicillin. it takes a carboxylic acid and attaches a nucleophile in the OH’s place
what do transpeptidase mutations lead to
bacteria develop resistance to penicillin. bacteria evolve ways to actively transport penicillin out of the cell/destroy the penicillin
what is β-lactamase and how does it affect the activity of penicillin
- β-lactamase is an enzyme evolved to open β-lactam ring of penicillin
- if you do not have the β-lactam then the penicillin is useless
- overtime bacteria changed the structure of the β-lactamase and made is optimal to wreck penicillin
when did β-lactamase first appear
1960s
explain the normal function of penicillin in normal bacteria cells vs the function of penicillin in resistant bacteria cells
- normal bacteria: if you have penicillin near transpeptidase it makes a covalent bond formed between them → non-functional enzyme (this is because there needs to be an OH group there to catalyze the reaction)
- when you a have resistant bacteria: it secretes β-lactamase outside the area of the bacteria and as the penicillin gets close, the β-lactamase will open the ring and make it non-functional
what change can be made to penicillin to kill the resistant bacteria and how does it work
substitute a large heterocycle onto the penicillin. this causes the molecule to adopt a conformation that does not allow them to enter the active site of the β-lactamase.
compare the structure of a normal penicillin molecule vs a penicillin with a large substituted heterocycle
in normal penicillin: double bond character makes molecule flat
in sub. penicillin:if large groups are put in the ortho position, this will make the bond between the heterocycle and the double bonded O rotate by 90º → flip the aromatic ring and take it out if the plane. the molecule becomes 3D = not able to fit in active site
explain how a shield provides selectivity with respect to transpeptidase and β-lactamase
- it is okay to attach a big shield because transpeptidase has a large pocket that will accommodate for it = able to inhibit transpeptidase
- it is not okay to attach a big shield because β-lactamase does not have a large pocket and it cannot accommodate this = do not have to worry about the drug getting targeted by β-lactamase
what are the two general types of bacteria
- Gram positive (blue)
- Gram negative (red)
what bacteria were the original penicillins active against
only gram positive = narrow spectrum of activity
compare the structure of gram positive bacteria vs gram negative bacteria
gram positive: because cell wall is on the outside, penicillin can easily get access to it and precent the transpeptidase from reacting
gram negative: surrounded by lipopolysaccharide layer: layer of slime that bacteria is coated in. extremely lipophilic and penicillin cant penetrate the layer very well. as a consequence it never gets to the cell wall. this is why original penicillin does not work on gram negative.
what discovery was made that allowed molecules to transport through the lipid layer of the gram negative bacteria
branched groups on left hand side = access to cell wall
why does poor water solubility result in poor bioavailability
poor absorption from the enzyme
what is a zwitterion and why does it not dissolve well in water
ion with both negative and positive charges. the charges balance out → neutral charge overall = does not dissolve well in water
