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Antibiotics. Mechanism of Action and Resistance. Antimicrobial Action and Resistance. Definition, concept of selective toxicity Targets and mechanisms of action of the major antibacterial agents Mechanisms of resistance to antibacterial agents Evolution and spread of antibiotic resistance.

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antibiotics

Antibiotics

Mechanism of Action and Resistance

antimicrobial action and resistance
Antimicrobial Action and Resistance
  • Definition, concept of selective toxicity
  • Targets and mechanisms of action of the major antibacterial agents
  • Mechanisms of resistance to antibacterial agents
  • Evolution and spread of antibiotic resistance
antimicrobials
Antimicrobials
  • Low molecular weight substances active against microorganisms at low concentrations
  • Historically two types
    • Antibiotic - microbial origin
    • Antimicrobial - chemically synthesized
  • Antimicrobial chemotherapy
selective toxicity
Selective toxicity
  • Active against bacteria not host
  • Targets unique to microorganism
      • peptidoglycan
  • Metabolic pathway absence in vertebrates
      • folate biosynthesis
  • Microbial enzyme has higher affinity than vertebrate enzyme
      • dihydrofolate reductase
  • Structural differences between bacterial and eucaryotic component
      • ribosome, chromosomes
  • Antibiotic is only actively transported or activated by microbe
      • tetracyclines, amino glycosides, metronidazole
action of antimicrobial
Action of antimicrobial
  • Bacteriocidal
    • Irreversible
    • May or may not cause lysis
  • Bacteriostatic
    • Reversible
  • Generally characteristic of antibiotic
    • Dose
    • Organism
sites of action of main antibiotics
Sites of action of main antibiotics

Protein

synthesis

DNA biosynthesis

and replication

Peptidoglycan

biosynthesis

sites of antimicrobial action
Sites of antimicrobial action
  • Peptidoglycan synthesis
  • Protein synthesis
  • Nucleic acid synthesis
    • DNA replication
    • Transcription
  • Cytoplasmic membrane integrity
biosynthesis of peptidoglycan
Biosynthesis of Peptidoglycan
  • Synthesize precursors in cytoplasm
  • Transport of precursors across cell membrane
  • Addition of precursors to peptidoglycan
  • Cross-linking of peptidoglycan chains
biosynthesis of peptidoglycan10

NAG

NAM

peptide

Biosynthesis of Peptidoglycan

Synthesize precursors

in cytoplasm

Cytoplasm

Cytoplasmic

membrane

Transport of precursors

across cell membrane

Addition of precursors

to peptidoglycan

Cell wall

Cross-linking of

peptidoglycan chains

biosynthesis of peptidoglycan11

NAG

NAM

Cycloserine

peptide

Bacitracin

Glycopeptides

b-Lactams

Glycopeptides

Biosynthesis of Peptidoglycan

Synthesize precursors

in cytoplasm

Transport of precursors

across cell membrane

Addition of precursors

to peptidoglycan

Cross-linking of

peptidoglycan chains

biosynthesis of peptidoglycan12
Biosynthesis of Peptidoglycan
  • Synthesize precursors in cytoplasm
    • Cycloserine
  • Transport of precursors across cell membrane
    • Bacitracin
  • Addition of precursors to peptidoglycan
    • Glycopeptides
  • Cross-linking of peptidoglycan chains
    • b-lactams, glycopeptides
protein synthesis inhibitors psi aminoglycosides

Inhibit initiation

Cause misreading of mRNA

Protein synthesis inhibitors (PSI): Aminoglycosides

Aminoglycosides, eg. Streptomycin, Gentamicin, Amikacin

NB. The only protein synthesis inhibitors that are bactericidal

psi chloramphenicol macrolides and lincosamides

Inhibit peptidyl transferase

Chloramphenicol

Macrolides

Lincosamides

Inhibit translocation

Macrolides

Lincosamides

PSI: Chloramphenicol, macrolides and lincosamides
protein synthesis inhibitors19

P

A

mRNA

5’

3’

Protein synthesis inhibitors

Nascent polypeptide

Chloramphenicol

50S

Macrolides, lincosamides

Tetracyclines

Aminoglycoside

30S

Direction of translation

70S ribosome

action of sulphonamides and trimethoprim
Action of sulphonamides and trimethoprim
  • Block the biosynthesis of folic acid
  • Folic acid is a co-factor in metabolism
  • Eg, needed in nucleic acid biosynthesis

Selective toxicity:

  • Most bacteria must synthesize folate de novo
  • They cannot use exogenous folate
  • Vertebrates cannot synthesize folate, it is a vitamin
action of sulphonamides and trimethoprim21

Sulphonamides

Trimethoprim

Dihydropteroate

Synthetase (DHPS)

Dihydrofolate

Reductase (DHFR)

Action of sulphonamides and trimethoprim

Para-amino benzoic acid (PABA)

Dihydropteroate

Dihydrofolate

Tetrahydrofolate

Nucleic acid synthesis

inhibitors of dna replication
Inhibitors of DNA replication
  • Quinolones and 4-fluoroquinolones
    • Naladixic acid, enrofloxacin, ciprofloxacin
    • Prevents introduction of negative supercoils
other antibiotics and their action
Other antibiotics and their action
  • Rifamycins
    • Transcription
    • E.g. Rifampicin – Imp. TB.
  • Polymyxins
    • Cell membrane, antimicrobial peptides
  • Nitroimidazoles
    • Disrupts DNA
    • Only active against anaerobes and protozoa
    • Metronidazole
    • Banned in food animals
anti fungals
Anti-fungals

Polyene antifungals

Amphotericin B , Nystatin

Bind ergosterol disrupt cell membrane

Cell wall

Cell membrane

Imidazoles

Miconazole, clotrimoxazole,

Ecoconazole, ketoconazole

Inhibit ergosterolbiosynthesis

Nucleus

5-flucytosine

Inhibit DNA & RNA

biosynthesis

Microtubules

Griseofulvin

Inhibit microtubule assembly