Antibiotics - 1/2 Flashcards
What are the different analogues of penicillin based on? How are they made?
semi-synthetic penicillins are based on 6-aminopenicillanic acid (6-APA)
are made via partial synthesis
What is the structure relationship of penicillins?
beta lactam ring (bicyclic ring)
- has 2 cis H atoms
= is essential for activity
acylamino side chain
free carboxylic acid
What is the structure of bacterial cell wall?
peptidoglycan cell wall
- is a mixed heteropolymer of hexose sugars and amino acids which surround the bacterium
hexose sugars are made up of N-acetylglucosamine (NAG) and N-acetylmuramic acid (NAM) linked alternatively in a chain
- polysaccharide
attached to NAM are short peptides
= L-ala, D-glu, L-lys, D-ala
joined by pentaglycyl (5 glycines)
What is the function of transamidase/penicillin binding protein (PBP)?
transamidase/PBP is an enzyme that cleaves between the two penultimate D-ala-D-ala amino acids at the end of N-acetylmuramic acid (NAM)
- enables attack by the free amino acid of a pentaglycyl to form a cross link joining of the bacterial cell wall
= enables attack by converting the 2nd D-ala into a different functional group
= the new ester group makes it susceptible to nucleophilic attack by neighbouring pentaglycyl chain and formation of an amide bond between them
What is the mechanism of action of penicillins?
penicillins inhibit transamidase/penicillin binding protein (PBP)
- blocks the crosslinking of polysaccharides chains
closely resembles acylated D-ala-D-ala
- acts as a substrate mimic
- binds irreversibly due to structural differences between penicillin and D-ala-D-ala
- reacts at the carbonyl group on PBP, opens it up to form an ester
- heterocyclic ring (thiazolidine ring) is thought to be a steric barrier for the approach of the pentaglycyl unit
= resulting cell wall is structurally weak leading to cell lysis and death
What are the problems associated with benzylpenicillin?
acid sensitive
- cannot be taken orally, must be given intravenously
not active over a wide spectrum of bacteria
- only effective against gram positive bacteria
sensitive to beta lactamases (enzyme)
- resistance occurs
Why is benzylpenicillin acid sensitive?
acid sensitive due to the presence of a cyclic amide with a strained ring system (acyl side chain)
- hydrolyses in the stomach via two mechanisms
intermolecular hydrolysis
- water reacts with the beta lactam ring
intramolecular reaction
- catalysed by acid
results in loss of the beta lactam ring therefore there is no activity
How can acid sensitivity of benzylpenicillin be overcome?
incorporating a side chain R group that is electron withdrawing
- e.g phenoxymethyl penicillin, fluorine, chlorine, nitro group, amide group
is introduced onto the amide in the 6 position
- reduces nucleophilicity of the intermediate which makes it less able to react with the beta lactam ring
increases bioavailability so can be given orally
How can the narrow spectrum of activity of benzylpenicillin be overcome?
addition of a polar group increases penetration across the outer membrane of gram negative bacteria
- must be incorporated on the alpha carbon to the carbonyl (1st carbon after the carbonyl)
- e.g amine, carboxylic acid, heteroatoms, sulphonic acid
= allows penicillin to pass through porins in the outer membrane more easily (cell wall is between the outer and inner cell membrane)
How is the problem of beta lactamases overcome for benzylpenicillin?
addition of bulky groups
- must be directly attached to the amidic carbonyl (must only be one carbon unit away from the carbonyl)
= provide steric hinderance
- ortho groups on a ring system attached directly to side chain carbonyl increases stability/resistance against beta lactamases
