Antibiotics : mode of action
Patrick TRIEU-CUOT, Prof.
Unité Biology of Gram Positive Pathogens
Institut Pasteur
Antibiotics
Antibiotics, or anti-bacterial agents, are low-molecular weight compounds
that interfere with the bacterial growth
Ø Most antibiotics are produced by microorganisms :
Streptomyces sp. and fungi
Penicillin G
=>
Penicillum chrysogenum
=>
Penicillum notatum
Streptomycin
=>
Bacillus brevis
Streptomyces griseus
Tetracycline
=>
Streptomyces aureofaciens
Chloramphenicol =>
Streptomyces venezuelae
Erythromycine =>
Streptomyces erythreus
Ø Some antibiotics are chemically syntesized :
Quinolones
Sulfonamides
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Antibiotics
Ø The biosynthesis of an antibiotic by a given micro-organism
confers to it a selective advantage towards susceptible
bacterial species by inhibiting their growth, in particular in
an environment with limiting natural resources.
Ø They are therefore very ancient molecules and the ability of
certain micro-organisms to synthesize them results from a
long evolutionary process.
Ø However, penicillin, produced by the mold Penicillium
chrysogenum, was characterized in 1929 whereas
sulfonamides was chemically synthesized in 1935.
Ø Antibiotics were introduced in human medicine in the
1940s.
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Classification
Antibiotics could be classified according to :
Ø Name of the molecule, different from the commercial
name
Ø Chemical structure (penicillins, glycopeptides,
aminoglycosides, macrolides, ...)
Ø Mode of action (cell wall inhibitors, protein synthesis
inhibitors)
Structurally related antibiotics interact with the same target,
as this could be the case for unrelated molecules.
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Mode of action
ka
Ab + Target
Ab-Target
kd
Ø The target is an enzyme or protein essential for the
bacterial growth.
Ø The Ab-target complex is inactive.
Ø The association constant (Ka) is by far greater than the
dissociation constant (Kd).
Ø The bacterial target should preferably be absent in
mammal cells or should specifically bind the antibiotic.
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Metabolism, cell growth and bacterial cell cycle
DNA
Replication
Transcription
RNA
Translation
Proteins
Non-essential functions
Essential functions
DNA synthesis
RNA synthesis
Protein synthesis
Cell wall synthesis
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Metabolism, cell growth and bacterial cell cycle
Gram-negative
DNA
RNA
Gram-positive
OM
CW
Mb
2
3
1
1
Porine
Ribosome
Protein
1: Cell wall synthesis
2: Nucleic acid synthesis (DNA or RNA)
3: Protein synthesis
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2
3
Inhibitors of cell wall synthesis
Peptidoglycan is a complex tridimensional polymer made of glycan strands
cross-linked by short peptides that surrounds the cytoplasmic membrane
Ø Beta-lactams inhibit the transpeptidation reaction :
penicillins
cephalosporins
carbapenems
Ø Glycopeptides inhibit the transglycosylation and transpeptidation
reactions :
teicoplanin
vancomycin
Membrane integrity :
Daptomycin
Polymyxin B
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Inhibitors of nucleic acid synthesis
Ø Synthesis of DNA precursor :
sulfonamides (DHPS), trimethoprim (DHFR)
Ø DNA Synthesis (DNA gyrase) :
quinolones (nalidixic acid)
fluoroquinolones (pefloxacin, ciprofloxacin)
Ø DNA integrity :
metronidazol
Ø RNA synthesis (RNA polymerase) :
rifampin
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Inhibitors of protein synthesis
The ribosome is a complex macromolecule made of two subunits
that directs protein synthesis.
Ø Ribosomal 30S subunit :
tetracyclines, tigecycline
aminoglycosides (gentamicin, amikacin, tobramycin,
streptomycin)
Ø Ribosomal 50S subunit :
chloramphenicol
macrolides, lincosamides, streptogramins
linezolid
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Effects on bacteria
Ø Antibiotics could either kill the bacteria or inhibit their growth.
Ø Antibiotics interfering with cell wall synthesis and nucleic acid
synthesis are generally bactericidal.
Ø Antibiotics inhibiting protein synthesis are mostly bacteriostatic
with the remarkable exception of aminoglycosides.
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