Week 10: Drugs for infection
Antibacterial drugs
Need selective toxicity: toxic to bacteria but innocuous in human host.
Can be bactericidal i.e. kill bacterium, or bacteriostatic i.e. stop bacterium growing.
Paul Ehrlich (1854-1915): Magic bullet – arsenic, Salvarsan
Alexander Fleming (1881-1955): Penicillin
Targets for antibacterial drugs:
o
Gram-positive:
o 20-atmosphere internal pressure
o Multi-layered peptidoglycan (up to 40 layers)
o Simple cell wall structure: 50% peptidoglycan, ~40% acidic polymer (polar – favours
penetration of positively-charged antibacterial drugs)
Gram-negative:
o 5-atmosphere internal pressure
o Single layer of peptidoglycan
o Thinner, more complex cell wall structure:
o Outer membrane that connects to a single layer of peptidoglycan. Outer membrane
consists of porins, through which hydrophilic antibacterial drugs move freely.
o Complex polysaccharides form endotoxins that determine the antigenicity of the
organism.
Lipopolysaccharide of the cell wall is a major barrier to penetration by benzylpenicillin,
methicillin, macrolides, rifampicin, fusidic acid and vancomycin.
Formation of the bacterial peptidoglycan cell wall, a single peptidoglycan chain is cross-
linked to other peptidoglycan chains through the action of the enzyme DD-transpeptidase.
o
Bacterial protein synthesis:
, o
o P site contains the growing peptide chain attached to a molecule of tRNA. The next
amino acid residue to be added – linked to its specific tRNA, with its distinctive
anticodon – moves into the A site, being bound to the site by codon : anticodon
recognition.
o Transpeptidation occurs, linking the peptide chain on the tRNA at the P site to the
amino acid on the incoming tRNA at the A site.
o The tRNA denuded of its peptide chain is ejected and the tRNA with peptide
attached in the A site is translocated to the P site. The ribosome then moves on one
codon on the mRNA (a new tRNA with attached amino acid can now move into the A
site).
Resistance to antibacterial drugs e.g. penicillin
o Causes:
Mutations of bacterial chromosomal genes
Extrachromosomal plasmid resistance genes – transposons (transfer of DNA
between plasmids)
Transfer of resistance genes between bacteria by conjugation or phages.
o Biochemical mechanisms:
production of enzymes that inactivate the antibiotic e.g. beta-lactamase,
acetyltransferases, kinases
modification of drug-binding sites
alteration of target enzymes e.g. DD-transpeptidase,
decreased accumulation of the antibiotic in bacterium by plasmid-mediated
efflux with reduced penetration
Antibiotic discovery (to combat bacterial resistance):
o Accidental observations e.g. Penicillin
o Drug design based on theory e.g. Salvarsan
o Systematic search in nature e.g. streptomycin
Drug Mechanism of action Other details
Affect peptidoglycan synthesis
Penicillins (beta-lactam Binds beta-lactam ring of penicillin to Side effects: Allergy and
antibiotic – beta-lactam ring DD-transpeptidase, inhibiting its anaphylaxis. Resistance
present in structure) e.g. cross-linking activity and preventing (by production of beta-
beta-lactamase-sensitive new bacterial cell wall formation. lactamases, which disrupt
benzylpenicillin, beta- The effect is to weaken the corset the beta-lactam ring.
Antibacterial drugs
Need selective toxicity: toxic to bacteria but innocuous in human host.
Can be bactericidal i.e. kill bacterium, or bacteriostatic i.e. stop bacterium growing.
Paul Ehrlich (1854-1915): Magic bullet – arsenic, Salvarsan
Alexander Fleming (1881-1955): Penicillin
Targets for antibacterial drugs:
o
Gram-positive:
o 20-atmosphere internal pressure
o Multi-layered peptidoglycan (up to 40 layers)
o Simple cell wall structure: 50% peptidoglycan, ~40% acidic polymer (polar – favours
penetration of positively-charged antibacterial drugs)
Gram-negative:
o 5-atmosphere internal pressure
o Single layer of peptidoglycan
o Thinner, more complex cell wall structure:
o Outer membrane that connects to a single layer of peptidoglycan. Outer membrane
consists of porins, through which hydrophilic antibacterial drugs move freely.
o Complex polysaccharides form endotoxins that determine the antigenicity of the
organism.
Lipopolysaccharide of the cell wall is a major barrier to penetration by benzylpenicillin,
methicillin, macrolides, rifampicin, fusidic acid and vancomycin.
Formation of the bacterial peptidoglycan cell wall, a single peptidoglycan chain is cross-
linked to other peptidoglycan chains through the action of the enzyme DD-transpeptidase.
o
Bacterial protein synthesis:
, o
o P site contains the growing peptide chain attached to a molecule of tRNA. The next
amino acid residue to be added – linked to its specific tRNA, with its distinctive
anticodon – moves into the A site, being bound to the site by codon : anticodon
recognition.
o Transpeptidation occurs, linking the peptide chain on the tRNA at the P site to the
amino acid on the incoming tRNA at the A site.
o The tRNA denuded of its peptide chain is ejected and the tRNA with peptide
attached in the A site is translocated to the P site. The ribosome then moves on one
codon on the mRNA (a new tRNA with attached amino acid can now move into the A
site).
Resistance to antibacterial drugs e.g. penicillin
o Causes:
Mutations of bacterial chromosomal genes
Extrachromosomal plasmid resistance genes – transposons (transfer of DNA
between plasmids)
Transfer of resistance genes between bacteria by conjugation or phages.
o Biochemical mechanisms:
production of enzymes that inactivate the antibiotic e.g. beta-lactamase,
acetyltransferases, kinases
modification of drug-binding sites
alteration of target enzymes e.g. DD-transpeptidase,
decreased accumulation of the antibiotic in bacterium by plasmid-mediated
efflux with reduced penetration
Antibiotic discovery (to combat bacterial resistance):
o Accidental observations e.g. Penicillin
o Drug design based on theory e.g. Salvarsan
o Systematic search in nature e.g. streptomycin
Drug Mechanism of action Other details
Affect peptidoglycan synthesis
Penicillins (beta-lactam Binds beta-lactam ring of penicillin to Side effects: Allergy and
antibiotic – beta-lactam ring DD-transpeptidase, inhibiting its anaphylaxis. Resistance
present in structure) e.g. cross-linking activity and preventing (by production of beta-
beta-lactamase-sensitive new bacterial cell wall formation. lactamases, which disrupt
benzylpenicillin, beta- The effect is to weaken the corset the beta-lactam ring.
