Antibiotics Flashcards
(32 cards)
What do all penicilins contain?
A Beta Lactam ring.
What is a B-lactam?
A B-lactam is a 4-membered cyclic amide.
considered as derived from an amino acid
Why is B-lactam ring an amide?
Amide because the ring contains a C=O-NH group.
What was the first clinically used penicillin and what was the issue with it?
The first clinically used penicillin was benzyl penicillin aka Penicillin G.
This penicillin is acid unstable and rapidly degrades in stomach acid. Hence only used for topical use e.g. WW2.
What are the 4 essential components required for penicillin to exert activity?
- B-lactam ring
- Free carboxylic acid - stereochemistry dashed lines (bond going into paper)
- Strained bicyclic ring - 4 membered ring fused to 5 membered ring
- Acylamino side chain - stereochemistry black wedge (bond towards you)
What can be changed in a basic penicillin structure?
R group attached to the acylamino side chain can be changed. The rest of the structure of the molecule is needed to bind to the bacterium.
What structure/compound can be used as a starting point to make penicillin antibiotics?
6-APA = 6-aminopenicillanic acid used as starting compound but it does not have the acylamino side chain.
Hence acyl side chain R group can be added synthetically via chemical reaction.
What does the term ‘chemically strained’ mean in terms of the bicyclic ring in the penicillin structure?
The fusion of the 4 membered ring with a 5 membered ring causes an instability which exists between the bonds. This makes the molecule reactive hence has good activity against bacteria.
How are semi-synthetic penicillins made?
General structure of penicillins are made using 6-APA with a suitable acetylating agent. 6-APA is made by fungi using fermenters. Then R group added synthetically by synthetic chemists.
Bacteria produce transpeptidase. Where is this found? What is the function of this enzyme?
Transpeptidase is found at the cell membrane in large quantities. It is an enzyme which catalyses crosslinking of peptidoglycan essential to form a cell wall.
What is the mechanism of action of B-lactam antibiotics?
B-lactam antibiotics bind and react with transpeptidase enzyme produced by bacteria to inhibit cell wall synthesis. No cell wall means that water can penetrate through the cell and cause it to lyse.
What is the rule for R group size?
The smaller the R group, the greater the activity.
Why would some penicillins be inactive against bacteria?
Bacteria can be resistant to some penicillins due to bacterial enzymes.
B-lactamase - breaks open the B-lactam ring via acid hydrolysis and deactivates the penicillin.
Penicillin amidase - cleaves the amide bond acyl side chain and deactivates the penicillin.
What can be done to the structure of penicillin to prevent B-lactamase enzymes degrading the antibiotic?
Increasing the steric bulk/size of the R group decreases the ability of the B-lactamase enzymes to bind to the penicillin.
What is the problem in using a bulky R group which prevents B-lactamase degrading the penicillin?
A large R group very significantly reduces the activity of the penicillin against transpeptidase.
So only use a bulky R group when required, to be effective.
Big R group
Blocks B-lactamase which stops the bacterium from destroying the penicillin drug but it is important to retain its activity against transpeptidase to kill the bacterium.
Describe the ideal penicillin analogue which can block B-lactamase activity while retaining activity against transpeptidase?
An ortho-disubstituted phenyl ring with small substituents is the ideal size.
What does broad spectrum mean?
Works against both Gram+ and Gram-.
What can happen to the B-lactam ring in acidic conditions?
The B-lactam ring is susceptible to an intramolecular ring opening reaction which deactivates the antibiotic. Thus, the ring cannot bind to transpeptidase.
How can acid stability of an antibiotic be increased? How does this work?
Ensure that the R group is an electron-withdrawing group. The inductive effect will draw electron density away from the carbonyl oxygen - reduces its tendency to act as a nucleophile. Prevents the ring opening.
Describe the intramolecular ring opening reaction which occurs in acidic conditions?
The degradation of the penicillin in acidic conditions involves the nucleophilic attack from the oxygen of the acylamino side chain carbonyl group at the carbon of the B-lactam ring carbonyl group. This causes a partial delta- charge at the oxygen and delta+ charge at carbon = a bond forms - forming a different ring structure. The B-lactam ring is opened leading to the destruction of the antibiotic.
Why would some penicillins show a poor activity against Gram negative bacteria?
- G- bacteria have an inner and outer membrane and the transpeptidase is found in the inner membrane which is difficult to reach.
- G- bacteria have a coating on the surface of the cell wall which is impermeable to penicillins.
- Some G- bacteria produce large amounts of transpeptidase which must be broken down.
- It is common to find transpeptidase mutations in G- bacteria.
How must penicillin reach transpeptidase in the inner cell membrane in the case of Gram- bacteria?
The penicillin must diffuse through channels in the outer membrane formed by porin proteins to reach the inner membrane.
What are porin channels?
Porin channels are channels used by the bacterium to bring in nutrients or excrete waste materials.
The inner part of the porin channels are lined with charge hence very highly polar.
