Beta-Lactam Antibiotics
The bacterial cell:
Gram positive bacteria – has a thick peptidoglycan cell wall (20-40nm in thickness) surrounding the
plasma membrane. The gram stain is purple as it absorbs the dye.
Gram negative bacteria – has a thin cell wall covered by a complex outer membrane, consisting of
lipoprotein and lipopolysaccharides. The cell wall is made up of outer and inner lipid bilayer
membranes and peptidoglycan. Its thickness is 2-7nm.
Mechanisms of antibacterial action:
• Inhibition of cell metabolism – sulphonamides (antimetabolite)
• Inhibition of cell wall synthesis – penicillins, cephalosporins, beta-lactamase inhibitors
• Interaction with the plasma membrane – polymyxins, valinomycin
• Disruption of protein synthesis (translation) – tetracyclines
• Inhibition of nucleic acid transcription and replication – quinolones
Inhibiting cell metabolism - Sulphonamides
• Prontosil (a pro-drug requiring activation) has antimicrobial properties – but only in-vivo. Upon
its metabolism, sulphanilamide is formed.
✓ Effective against many Gram positive organisms such as pneumococci and meningococci.
Ineffective against salmonella and yields toxic metabolites
SAR of Sulphonamides:
1. Amino groups and sulphonamide must be directly attached to the aromatic ring
2. Aromatic ring and sulphonamide group are both required
3. Para-amino group is essential and must be unsubstituted (except when R1 is an acyl (amide) i.e.
amino group is not needed when an amide is present)
4. The aromatic ring must be para-substituted (positions 1, 4) only
5. The sulphonamide nitrogen must be primary (1 hydrogen) or secondary (2 hydrogens)
6. R2 is the only possible site for variation
,Sulphonamides: Reducing the toxicity
• Sulfathiazole is metabolised via acetylation to form an amide which is insoluble in water.
• This amide can be fatal if it blocks the kidney tubules.
• Metabolism of the sulfathiazole differs within the population i.e. people of Chinese or Japanese
descent have a faster metabolism and are thus more likely to suffer kidney problems.
1. By modulating the acidity of the sulphonamide proton, the solubility can be improved.
2. Sulphonamides are more acidic than amides as sulphur has 2 double bonds to oxygen whereas
the amide only has a carbonyl group.
3. A heterocycle group with an electron-withdrawing ability can be added to the R2 position to
increase the acidity and subsequently increase solubility.
4. This stabilises the structure as oxygens are closer by and there is negative charge on the oxygen.
Presence of a charge means it remains soluble despite acetylation.
5. This structure is 86% ionised and more water soluble due to the more acidic sulphonamide NH.
Sulphonamides: Applications
- used for the Tx of UTIs and gut infections, as eye lotions and for mucous membrane infections.
Benzoyl derivative
• As the succinate cannot cross the gut wall, it can stay in the gut to treat the infection.
• The benzyl derivative is insoluble and hydrophobic which means it will also stay in the gut and
fight infection.
Sulphonamides: Mechanism of Action
, 1. Sulphonamides competitively and reversibly inhibit the dihydropteroate synthetase enzyme,
which is responsible for adding para-aminobenzoic acid (PABA) to dihydropteroate diphosphate
to form dihydropteroate. The structures of sulphonamides and PABA are similar which allows
the sulphonamide to competitively (but reversibly) inhibit dihydropteroate synthetase.
2. This inhibition stops DNA formation at an early process as tetrahydrofolate cannot be made.
3. Tetrahydrofolate is required by all cells because it donates 2 carbon fragments for the formation
of pyrimidines which are subsequently used in the formation of DNA.
4. Resistance can occur if more PABA is produced by the bacteria, As the inhibition is competitive
(i.e. sulphonamides displace PABA), this resistance is concentration-dependent.
Trimethoprim – works against dihydrofolate reductase to inhibit DNA synthesis and cell growth.
Co-trimoxazole – this has a two-fold effect as it’s a combination of trimethoprim and
sulfamethoxazole. It stops the incorporation of para-aminobenzoic acid into dihydropteroate and
also inhibits dihydrofolate reductase. This means two enzymes are inhibited in the same pathway.
This is known as ‘sequential blocking’.
Inhibiting cell wall synthesis: Penicillins
• The first penicillins were penicillin G and penicillin V.
• The R group can be varied, depending on the acid present in the fermentation medium. For
example, if phenyl-acetic acid is present, penicillin G can be produced.
• Addition of different carboxylic acids to the fermentation medium can result in different acyl
side chains, i.e. penicillin V.
• However, this is a limited
method as only acids with
the formula RCH2COOH
can be added.
The bacterial cell:
Gram positive bacteria – has a thick peptidoglycan cell wall (20-40nm in thickness) surrounding the
plasma membrane. The gram stain is purple as it absorbs the dye.
Gram negative bacteria – has a thin cell wall covered by a complex outer membrane, consisting of
lipoprotein and lipopolysaccharides. The cell wall is made up of outer and inner lipid bilayer
membranes and peptidoglycan. Its thickness is 2-7nm.
Mechanisms of antibacterial action:
• Inhibition of cell metabolism – sulphonamides (antimetabolite)
• Inhibition of cell wall synthesis – penicillins, cephalosporins, beta-lactamase inhibitors
• Interaction with the plasma membrane – polymyxins, valinomycin
• Disruption of protein synthesis (translation) – tetracyclines
• Inhibition of nucleic acid transcription and replication – quinolones
Inhibiting cell metabolism - Sulphonamides
• Prontosil (a pro-drug requiring activation) has antimicrobial properties – but only in-vivo. Upon
its metabolism, sulphanilamide is formed.
✓ Effective against many Gram positive organisms such as pneumococci and meningococci.
Ineffective against salmonella and yields toxic metabolites
SAR of Sulphonamides:
1. Amino groups and sulphonamide must be directly attached to the aromatic ring
2. Aromatic ring and sulphonamide group are both required
3. Para-amino group is essential and must be unsubstituted (except when R1 is an acyl (amide) i.e.
amino group is not needed when an amide is present)
4. The aromatic ring must be para-substituted (positions 1, 4) only
5. The sulphonamide nitrogen must be primary (1 hydrogen) or secondary (2 hydrogens)
6. R2 is the only possible site for variation
,Sulphonamides: Reducing the toxicity
• Sulfathiazole is metabolised via acetylation to form an amide which is insoluble in water.
• This amide can be fatal if it blocks the kidney tubules.
• Metabolism of the sulfathiazole differs within the population i.e. people of Chinese or Japanese
descent have a faster metabolism and are thus more likely to suffer kidney problems.
1. By modulating the acidity of the sulphonamide proton, the solubility can be improved.
2. Sulphonamides are more acidic than amides as sulphur has 2 double bonds to oxygen whereas
the amide only has a carbonyl group.
3. A heterocycle group with an electron-withdrawing ability can be added to the R2 position to
increase the acidity and subsequently increase solubility.
4. This stabilises the structure as oxygens are closer by and there is negative charge on the oxygen.
Presence of a charge means it remains soluble despite acetylation.
5. This structure is 86% ionised and more water soluble due to the more acidic sulphonamide NH.
Sulphonamides: Applications
- used for the Tx of UTIs and gut infections, as eye lotions and for mucous membrane infections.
Benzoyl derivative
• As the succinate cannot cross the gut wall, it can stay in the gut to treat the infection.
• The benzyl derivative is insoluble and hydrophobic which means it will also stay in the gut and
fight infection.
Sulphonamides: Mechanism of Action
, 1. Sulphonamides competitively and reversibly inhibit the dihydropteroate synthetase enzyme,
which is responsible for adding para-aminobenzoic acid (PABA) to dihydropteroate diphosphate
to form dihydropteroate. The structures of sulphonamides and PABA are similar which allows
the sulphonamide to competitively (but reversibly) inhibit dihydropteroate synthetase.
2. This inhibition stops DNA formation at an early process as tetrahydrofolate cannot be made.
3. Tetrahydrofolate is required by all cells because it donates 2 carbon fragments for the formation
of pyrimidines which are subsequently used in the formation of DNA.
4. Resistance can occur if more PABA is produced by the bacteria, As the inhibition is competitive
(i.e. sulphonamides displace PABA), this resistance is concentration-dependent.
Trimethoprim – works against dihydrofolate reductase to inhibit DNA synthesis and cell growth.
Co-trimoxazole – this has a two-fold effect as it’s a combination of trimethoprim and
sulfamethoxazole. It stops the incorporation of para-aminobenzoic acid into dihydropteroate and
also inhibits dihydrofolate reductase. This means two enzymes are inhibited in the same pathway.
This is known as ‘sequential blocking’.
Inhibiting cell wall synthesis: Penicillins
• The first penicillins were penicillin G and penicillin V.
• The R group can be varied, depending on the acid present in the fermentation medium. For
example, if phenyl-acetic acid is present, penicillin G can be produced.
• Addition of different carboxylic acids to the fermentation medium can result in different acyl
side chains, i.e. penicillin V.
• However, this is a limited
method as only acids with
the formula RCH2COOH
can be added.
