MECHANISMS OF ACTION OF ANTIBIOTICS

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MECHANISMS OF ACTION OF ANTIBIOTICS
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BACTERIOSTATIC AGENTS

• Sulfonamides
• Drugs inhibiting protein synthesis except
  aminoglycosides (macrolides, chloramphenicol,
  tetracyclines etc).

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BACTERICIDAL AGENTS

• Beta lactams (penicillins, cephalosporins,
  imipenem)
• Trimethoprim/sulfamethoxazole
• Vancomycin
• Fluoroquinolones
• Aminoglycosides

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MECHANISMS OF ACTION

• Inhibitors of cell wall synthesis
• Drugs altering cell membranes
• Inhibitors of protein synthesis
• Antimetabolites
• Inhibitors of nucleic acid synthesis.

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DRUGS INHIBITING CELL WALL SYNTHESIS

• Penicillins
• Cephalosporins
• Imipenem
• Vancomycin
• Fosfomycin

ß-lactams
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www.uccs.edu/
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www.chem.qmul.ac.uk/
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www.uccs.edu/
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Glycopeptide Polymer
Mur NAc
X
Glycopeptide Polymer
X
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Penicillin Binding Proteins
Transpeptidases
Penicillin
Carboxypeptidases
Endopeptidases
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AUTOLYSINS
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• All Beta lactam antibiotics act by the same
  mechanism

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PENICILLINS ACTIVE VS GRAM - BACTERIA
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S
CH3
O
C
CH3
N
C
R
C
C
C
C
N
COOH
O
Penicillinase
(ß-Lactamase)
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COMBINATIONS WITH BETA LACTAMASE INHIBITORS

• Penicillin plus a beta lactamase inhibitor.

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CEPHALOSPORINS AND IMIPENEM

• Same mechanism of action as penicillins but bind
  to different binding proteins.

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FOSFOMYCIN

• Inhibits peptidoglycan synthesis at an earlier
  stage than where the beta lactams act.

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(Biel pp 24-26)
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VANCOMYCIN
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Transpeptidase
PENICILLINS
X
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Transglycosylase
VAN
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RESISTANCE TO BETA LACTAMS

• Penicillinase
• Beta lactamases

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RESISTANCE

• Increased production of beta-lactamase
  (penicillinase) enzymes.

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S
CH3
O
C
CH3
N
C
R
C
C
C
C
N
COOH
O
Penicillinase
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METHICILLIN RESISTANCE

• Altered PBPs.

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RESISTANCE TO OTHER BETA LACTAM ANTIBIOTICS

• Most prevalent mechanism is hydrolysis by beta
  lactamases.
• Cephalosporins have variable susceptibility to
  ßlactamases.
• Some even induce formation of the enzymes.

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RESISTANCE TO VANCOMYCIN
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ANTIBIOTICS AFFECTING CELL MEMBRANES

• Polymyxins
• Daptomycin

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POLYMYXINS

• Surface active amphipathic agents.
• Interact strongly with phospholipids and disrupt
  the structure of cell membranes.

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DAPTOMYCIN

• Depolarizes the cell membrane

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ANTIBIOTICS INHIBITING PROTEIN SYNTHESIS

• Macrolides
• Clindamycin
• Linezolid
• Streptogramins
• Chloramphenicol
• Tetracyclines
• Aminoglycosides

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Procaryotic Ribosome
70S--M.W.2,500,000
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Antibiotics binding to the 50S ribosomal subunit
and inhibiting protein synthesis

• Erythromycin and other macrolides
• Chloramphenicol
• Linezolid
• Streptogramins

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Antibiotics binding to the 30S ribosomal subunit
and inhibiting protein synthesis

• Aminoglycosides
• Tetracyclines

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CLEanS AT
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Macrolides (Erythromycin, Azithromycin and
Clarithromycin)
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MACROLIDES
TRANSLOCATION
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CHLORAMPHENICOL
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A
50S
Nascent polypeptide chain
Transferase site
aa
mRNA
template
P
30S
Mechanism of action of Chloramphenicol
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INITIATION
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STREPTOGRAMINS

• Quinupristin/Dalfopristin (3070)

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DALFOPRISTIN
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MECHANISM OF ACTION

• Act synergistically to inhibit bacterial protein
  synthesis.
• They bind to separate sites on the 50 S ribosomal
  subunit and form a ternary complex with the
  ribosome.

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MECHANISM OF ACTION

• Quinupristin binds at the same site as the
  macrolides and has a similar effect.
• Dalfopristin directly blocks peptide bond
  formation by inhibiting peptidyl transferase.
• Dalfopristin results in a conformational change
  in the 50S ribosome subunit.

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INITIATION
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AMINOGLYCOSIDES

• Bind irreversibly to the 30S subunit.
• Exact mechanism of cell death is unknown.
• Postantibiotic effect.

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A
50S
Nascent polypeptide chain
Transferase site
mRNA
template
P
30S
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INHIBITION OF MITOCHONDRIAL PROTEIN SYNTHESIS

• Mitochondrial ribosome resembles bacterial
  ribosome.
• May account for some toxic effects (e.g.
  chloramphenicol, linezolid).

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RESISTANCE

• Alterations in ribosomal proteins (e.g.
  macrolides).
• Decreased permeability to the antibiotic.

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TETRACYCLINE RESISTANCE
ATP
Tetracycline
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ANTIBIOTICS ACTING AS ANTIMETABOLITES

• Sulfonamides
• Trimethoprim plus sulfamethoxazole

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FOLIC ACID BIOSYNTHESIS
DIHYDROPTERIDINE
2 ATP
PYROPHOSPHATE DERIVATIVE
Dihydropteroate Synthetase
2HN
COOH
DIHYDROPTEROIC ACID
Glutamic Acid
DIHYDROFOLIC ACID
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TRIMETHOPRIM-SULFAMETHOXAZOLE
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PABA
Pteridine
Dihydropteroate Synthetase
DIHYDROPTEROIC ACID
Dihydrofolate Synthetase
DIHYROFOLIC ACID
Dihydrofolate Reductase
TETRAHYDROFOLIC ACID
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• Advantages of sulfonamide-trimethoprim combination

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SULFONAMIDE-RESISTANCE

• Results from multiple mechanisms.
• Altered dihydropteroate synthetase.
• Cross-resistance among all sulfonamides.

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ANTIBIOTICS AFFECTING NUCLEIC ACID SYNTHESIS.

• Fluoroquinolones
• Metronidazole
• Rifampin

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FLUOROQUINOLONES
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FLUOROQUINOLONES

• Gyrase (Topoisomerase I)-older quinolones
• Topoisomerase IV-3rd and 4th gen quinolones.

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FQ RESISTANCE

• Changes in gyrase and topoisomerase
• Increased efflux

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Metronidazole
Mechanism of action of metronidazole on an
anaerobic organism
Metronidazole
Ferredoxin reduced
Short lived intermediates
DNA
RNA
Protein
Other targets
Inactive end products
Inactive End Products
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RIFAMPIN