MSOP1016: Science of Medicines 3 Antibacterial Agents Introduction & b-lactam antibiotics (Part 1)

Antibacterial Agents

• Antibacterial agents can be classified into several categories, including:
  • Inhibitors of cell metabolism (e.g. sulphonamides)
  • Inhibitors of cell wall synthesis (e.g. penicillins, cephalosporins, b-lactamase inhibitors, glycopeptides)
  • Inhibitors of nucleic acid transcription and replication (e.g. quinolones, aminoacridines)
  • Inhibitors of protein synthesis (e.g. aminoglycosides, macrolides, tetracyclines)

Sulphonamides

• Sulphonamides are a type of antimetabolite that inhibits cell metabolism
• The first synthetic antibacterial agent, prontosil, was discovered to have antibacterial properties in vivo
• Sulphanilamide was the first synthetic antibacterial agent active against a wide range of infections
• Sulphonamides are effective against Gram-positive organisms, but not against Salmonella, and can produce toxic metabolites
• The para-amino group is essential for activity and must be unsubstituted (except when R1 = acyl)
• Aromatic ring and sulphonamide group are both required, and must be directly attached to the aromatic ring
• The sulphonamide and amino groups must be directly attached to the aromatic ring, and the aromatic ring must be para-substituted only
• R2 is the only possible site for variation
• Reducing toxicity is a concern, as sulphonamides can be fatal if they block kidney tubules
• Population differences in metabolism can affect the efficacy of sulphonamides
• Increasing the solubility of sulphonamides can improve their effectiveness

Applications of Sulphonamides

• Sulphonamides are used to treat urinary tract infections, eye infections, mucous membrane infections, and gut infections
• They are particularly useful in treating gut infections

Mechanism of Action of Sulphonamides

• Sulphonamides work by inhibiting the enzyme responsible for the synthesis of folic acid, which is necessary for bacterial growth
• Trimethoprim acts against dihydrofolate reductase, inhibiting DNA synthesis and cell growth
• Cotrimoxazole, a combination of sulphamethoxazole and trimethoprim, inhibits two enzymes in the same biosynthetic pathway, known as "sequential blocking"

Penicillins

• Penicillins are a type of antibacterial agent that inhibits cell wall synthesis
• The discovery of penicillin is attributed to Alexander Fleming, who discovered the mold Penicillium notatum in 1928
• Penicillins were first isolated and purified in 1941, and the structure of penicillin was established using X-ray crystallography in 1945
• The first semi-synthetic penicillin was synthesized in 1957
• Penicillins can be synthesized by fermentation or semi-synthetic procedures
• The mechanism of action of penicillins involves the inhibition of the transpeptidase enzyme, which is responsible for the cross-linking reaction in bacterial cell wall synthesis
• The transpeptidase enzyme is a penicillin-binding protein (PBP)
• Penicillins work by binding to the PBP, inhibiting the cross-linking reaction and preventing bacterial cell wall synthesis

Resistance to Penicillins

• Bacterial resistance to penicillins can occur through several mechanisms, including:
  • Physical barriers, such as the presence of a cell wall or outer membrane
  • The production of b-lactamase enzymes, which can break down penicillins
  • Mutations and genetic transfers that affect the affinity of the transpeptidase enzyme for penicillins
  • The presence of porins, which can affect the transport of penicillins into the bacterial cell
• The production of b-lactamase enzymes is a major mechanism of resistance to penicillins
• There are over 1,000 types of b-lactamase enzymes, with different selectivity for penicillins and cephalosporins
• The concentration and affinity of the transpeptidase enzyme can also affect the susceptibility of bacteria to penicillins

Structure-Activity Relationships (SAR) of Penicillins

• The structure of penicillins is critical to their activity, with the b-lactam ring and acyl side chain being essential components
• The acid sensitivity of penicillins can be improved by reducing the neighbouring group participation
• The addition of hydrophobic groups to the side chain can improve the activity of penicillins against Gram-negative bacteria
• The addition of hydrophilic groups to the side chain can improve the activity of penicillins against Gram-positive bacteria
• The use of steric shields can protect penicillins from b-lactamase enzymes

Broader Spectrum of Penicillins

• The spectrum of activity of penicillins can be broadened by modifying the structure of the side chain
• The use of hydrophobic groups on the side chain can improve the activity of penicillins against Gram-negative bacteria
• The use of hydrophilic groups on the side chain can improve the activity of penicillins against Gram-positive bacteria
• The use of aminopenicillins, carboxypenicillins, and ureidopenicillins can improve the activity of penicillins against Gram-negative bacteria
• The use of synergistic combinations of penicillins with other antibacterial agents can improve their effectiveness