(PM3A) Chemistry of Antimicrobial Drugs Flashcards
With respect to antibiotics, which relevant cells have a cell wall and which do not?
Bacteria have a cell wall
Animal cells do NOT
What is the cell wall made from?
Co-polymer called peptidoglycan
What is peptidoglycan?
A co-polymer which forms the bacterial cell wall
How much peptidoglycan is there in a gram positive bacterial cell wall?
Thick layers
How much peptidoglycan is there in a gram negative bacterial cell wall?
1-2 molecular layers
Surrounded by a membrane
What are the sugar backbones in peptidoglycan?
(1) N-acetylglucosamine
(2) N-acetylmuramic acid
What is the composition of peptidoglycan?
(1) 2 sugar backbones
(2) Peptide chains composed of D-amino acids
What are the peptide chains in peptidoglycan composed of?
D-amino acids
What does a transpeptidase (TPase) enzyme do?
Catalyses a cross-linking reaction in the final stage of the biosynthesis of a bacterial cell wall
Which enzyme catalyses the cross-linking reaction in the final stage of bacterial cell wall biosynthesis?
Transpeptidase
TPase
Which type of antimicrobial inhibits an enzyme involved in the catalysis of cross-linking in the bacterial cell wall? What is this enzyme?
Penicillins
Transpeptidase (TPase)
Describe the structure of a penicillin.
- Four membered beta-lactam ring
- Fused to a 5 membered thiazolidine ring
How can penicillins be manufactured?
(1) Chemical synthesis
(2) Fermentation
(1) Which bacteria are penicillins normally active against?
(2) Give an example.
(1) Non beta-lactamase producing gram-positive bacilli
(2) e.g. meningitis
What is the range of responses had by those experiencing an allergic reaction to penicillin?
Rash -> Anaphylactic shock
Which functional groups of penicillin are essential to its function?
(1) Amide
(2) Lactam
(3) Free carboxylate
(1) What state is the free carboxylate of penicillin normally in?
(2) What effect does this have on the administration of penicillin?
(1) Usually ionised
(2) Usually administered as a sodium/ potassium salt
Give an example of a penicillin that is sensitive to acid?
Penicillin G
What reasons are there for penicillin G being sensitive to acid?
(1) Ring strain
(2) Amide side chain can open the beta-lactam ring
What does ‘ring strain’ mean, with reference to penicillin sensitivity to acid?
(1) Acid-catalysed ring opening relieves strain by opening the more highly strained beta-lactam ring
(2) Carbonyl group of lactam is more prone to nucleophilic attack
How are aqueous solutions of antibiotics prepared if they contain a beta-lactam ring?
(1) Supplied as dry powder
(2) Reconstituted immediately before being dispensed
Why are antibiotics containing a beta-lactam ring reconstituted just before dispensing?
Beta-lactams have general instability in aqueous solutions
What are the storage requirements for an antibiotic containing a beta-lactam?
Fridge storage
How long can an antibiotic containing a beta-lactam be stored for?
7 days (refrigerated)
What effect can the amide side chain of a penicillin have on the beta-lactam ring in the presence of acid?
- Can actively participate in a mechanism opening the beta-lactam ring in the presence of acid
(1) What happens if a penicillin is exposed to an acid?
(2) What effect does this have on the penicillin?
(1) Beta-lactam is destroyed
(2) Destroys functionality
ø Beta-lactam was essential for activity
What is the effect on the beta-lactam ring of a penicillin if the amide is more electron poor?
- Less of an ability to open the beta-lactam ring
- Amide is less nucleophilic
What difficulty does the sensitivity of penicillins to acid present?
Oral delivery route (stomach acid)
What is penicillin V?
Phenoxymethylpenicillin
What is another name for phenoxymethylpenicillin?
Penicillin V
Why is phenoxymethylpenicillin able to be administered orally, despite the sensitivity of penicillins to acid?
- The nucleophilicity of the amide chain is reduced
- Increases stability
- Sufficiently stable to exist in stomach
(1) Name 2 penicillins which can be given orally.
(2) Why can they be administered orally, where others cannot?
(1) Phenoxymethylpenicillin + ampicillin
(2) Greater acid stability due to decreased electron density (nucleophilicity) of the amide present in the penicillin
(1) Give one example of an acid sensitive penicillin?
(2) Why is it acid sensitive?
(1) Penicillin G
(2) Amide opens the beta-lactam ring (essential for activity of penicillin) in the presence of acid
What is the most common method of a bacteria gaining resistance to a penicillin?
Presence of beta-lactamase enzyme
How does beta-lactamase affect beta-lactam
Hydrolyses it
What is the penicillin called once the beta-lactam has been hydrolysed by an acid/ beta-lactamase?
Ring-opened penicillin
What is the function of ring-opened penicillin?
None. It is inactive
Where is beta-lactamase usually contained? Where else can it be observed and when?
(1) Usually present within the bacteria (gram-negative)
2) Can also be released into the surrounding environment (gram-positive
What caused the critical bacterial resistance issue in the 1960s?
- Over-use of penicillin G
- Led to an increase of penicillin-resistant Staph. aureus infections
Following the increase of bacterial penicillin resistance in the 1960s, what method was used to counter-act this?
Steric shields
- To block penicillin from fitting into the beta-lactamase enzymes of the resistant bacteria
What was the issue found when there was too much steric shielding implemented into the penicillin?
Inactivity of the penicillin
- Could not activate the transcriptidase target enzyme
What was the first semi-synthetic penicillin that had resistance to the beta-lactamase enzyme of S. aureus?
Methicillin
What is a beneficial change to the functional groups of penicillin to prevent binding of beta-lactamase?
Adding a spatially bulky functional group, can block binding to beta-lactamase
What are the key factors to consider for an effective and useful penicillin analogue?
(1) Acid resistant/ stable
(2) Sterically shielded
Why is methicillin not an ideal penicillin?
Has steric shielding (beta-lactamase is ineffective)
BUT is acid sensitive
What approaches can be used to prevent action of beta-lactamase with penicillin?
(1) Steric shielding
(2) Administration alongside a beta-lactamase inhibitor
What is the most effective beta-lactamase inhibitor?
Clavulanic acid
What is clavulanic acid?
Most effective beta-lactamase inhibitor
Why is clavulanic acid suitable as a beta-lactamase inhibitor
(1) Highly strained beta-lactam ring
How can acid sensitivity of a penicillin be reduced?
Addition of an electron withdrawing group on the amide side chain
What happens to a penicillin if the bulky side group added to prevent beta-lactamase binding (steric shielding) is too large?
Prevents binding to transpeptidase (TPase) target enzyme
(1) What type of penicillin are the aminopenicillins?
(2) Give 2 examples
(1) Broad-spectrum
(2) Ampicillin + amoxicillin
What is important, regarding penicillins, for good absorption through the gut wall?
No ionisation on side groups
Name 2 common types of antibiotic.
(1) Penicillins
(2) Cephalosporins
What is a similarity of cephalosporins to penicillins?
(1) Contain a 4 membered beta-lactam ring
What is the beta-lactam ring of a cephalosporin bound to that the beta-lactam of a penicillin is not?
6-membered dihydrothiazine ring
Which type of antibiotic has the greatest stability of the bicyclic system, cephalosporins or penicillins?
Cephalosporins
The adjacent 6-membered dihydrothiazide ring reduces the ring strain by a greater extent
What is the mechanism of action of the cephalosporins?
Inhibitor of the transpeptidase (TPase) enzyme
How does the activity of cephalosporin C compare to that of penicillin G?
Only about 1/1000 as active
What is a benefit of cephalosporin C over penicillin G, regarding activity?
Cephalosporin C has more of a balance of activity with gram-positive and gram-negative bacteria
Is cephalosporin C or penicillin G more resistant to beta-lactamase?
Cephalosporin C is more resistant to beta-lactamase
Is cephalosporin C or penicillin G more resistant to acid hydrolysis?
Cephalosporin C is more resistant to acid hydrolysis
What is a zwitterion?
A molecule with an equal number of negatively and positively charged functional groups
(1) What was a functional group of cephalosporins which was commonly changed and gradually phased out with each generational change?
(2) Why?
(1) Esters
(2) Esters were commonly cleaved by esterases. This was not optimal for effective antibiotic activity
