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Antibiotics: Protein Synthesis, Nucleic Acid Synthesis and Metabolism

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Title: Antibiotics: Protein Synthesis, Nucleic Acid Synthesis and Metabolism


1
Antibiotics Protein Synthesis, Nucleic Acid
Synthesis and Metabolism
2
Principles and Definitions
  • Selectivity
  • Selectivty8 toxicity9
  • Therapeutic index
  • Toxic dose/ Effective dose
  • Categories of antibiotics
  • Bactericidal
  • Usually antibiotic of choice
  • Bacteriostatic
  • Duration of treatment sufficient for host defenses

3
Principles and Definitions
  • Antibiotic susceptibility testing (in vitro)
  • Minimum inhibitory concentration (MIC)
  • Lowest concentration that results in inhibition
    of visible growth
  • Minimum bactericidal concentration (MBC)
  • Lowest concentration that kills 99.9 of the
    original inoculum

4
Antibiotic Susceptibility Testing
5
Zone Diameter Standards for Disk Diffusion Tests
6
Principles and Definitions
  • Combination therapy
  • Prevent emergence of resistant strains
  • Temporary treatment until diagnosis is made
  • Antibiotic synergism
  • Penicillins and aminoglycosides
  • CAUTION Antibiotic antagonism
  • Penicillins and bacteriostatic antibiotics
  • Antibiotics vs chemotherapeutic agents vs
    antimicrobials

7
Review of Initiation of Protein Synthesis
8
Review of Elongation of Protein Synthesis
9
Survey of Antibiotics
10
Protein Synthesis Inhibitors
  • Mostly bacteriostatic
  • Selectivity due to differences in prokaryotic and
    eukaryotic ribosomes
  • Some toxicity - eukaryotic 70S ribosomes

11
Antimicrobials that Bind to the 30S Ribosomal
Subunit
12
Aminoglycosides (bactericidal)streptomycin,
kanamycin, gentamicin, tobramycin, amikacin,
netilmicin, neomycin (topical)
  • Mode of action - The aminoglycosides irreversibly
    bind to the 16S ribosomal RNA and freeze the 30S
    initiation complex (30S-mRNA-tRNA) so that no
    further initiation can occur. They also slow
    down protein synthesis that has already initiated
    and induce misreading of the mRNA. By binding to
    the 16 S r-RNA the aminoglycosides increase the
    affinity of the A site for t-RNA regardless of
    the anticodon specificity. May also destabilize
    bacterial membranes.
  • Spectrum of Activity -Many gram-negative and some
    gram-positive bacteria Not useful for anaerobic
    (oxygen required for uptake of antibiotic) or
    intracellular bacteria.
  • Resistance - Common
  • Synergy - The aminoglycosides synergize with
    -lactam antibiotics. The -lactams inhibit cell
    wall synthesis and thereby increase the
    permeability of the aminoglycosides.

13
Tetracyclines (bacteriostatic)tetracycline,
minocycline and doxycycline
  • Mode of action - The tetracyclines reversibly
    bind to the 30S ribosome and inhibit binding of
    aminoacyl-t-RNA to the acceptor site on the 70S
    ribosome.
  • Spectrum of activity - Broad spectrum Useful
    against intracellular bacteria
  • Resistance - Common
  • Adverse effects - Destruction of normal
    intestinal flora resulting in increased secondary
    infections staining and impairment of the
    structure of bone and teeth.

14
Spectinomycin (bacteriostatic)
  • Mode of action - Spectinomycin reversibly
    interferes with m-RNA interaction with the 30S
    ribosome. It is structurally similar to the
    aminoglycosides but does not cause misreading of
    mRNA.
  • Spectrum of activity - Used in the treatment of
    penicillin-resistant Neisseria gonorrhoeae
  • Resistance - Rare in Neisseria gonorrhoeae

15
Antimicrobials that Bind to the 50S Ribosomal
Subunit
16
Chloramphenicol, Lincomycin, Clindamycin
(bacteriostatic)
  • Mode of action - These antimicrobials bind to the
    50S ribosome and inhibit peptidyl transferase
    activity.
  • Spectrum of activity - Chloramphenicol - Broad
    range Lincomycin and clindamycin -
    Restricted range
  • Resistance - Common
  • Adverse effects - Chloramphenicol is toxic (bone
    marrow suppression) but is used in the treatment
    of bacterial meningitis.

17
Macrolides (bacteriostatic)erythromycin,
clarithromycin, azithromycin, spiramycin
  • Mode of action - The macrolides inhibit
    translocation.
  • Spectrum of activity - Gram-positive bacteria,
    Mycoplasma, Legionella
  • Resistance - Common

18
Antimicrobials that Interfere with Elongation
Factors
Selectivity due to differences in prokaryotic and
eukaryotic elongation factors
19
Fusidic acid (bacteriostatic)
  • Mode of action - Fusidic acid binds to elongation
    factor G (EF-G) and inhibits release of EF-G from
    the EF-G/GDP complex.
  • Spectrum of activity - Gram-positive cocci

20
Inhibitors of Nucleic Acid Synthesis
21
Inhibitors of RNA Synthesis
Selectivity due to differences between
prokaryotic and eukaryotic RNA polymerase
22
Rifampin, Rifamycin, Rifampicin, Rifabutin
(bactericidal)
  • Mode of action - These antimicrobials bind to
    DNA-dependent RNA polymerase and inhibit
    initiation of mRNA synthesis.
  • Spectrum of activity - Wide spectrum but is used
    most commonly in the treatment of tuberculosis
  • Resistance - Common
  • Combination therapy - Since resistance is
    common, rifampin is usually used in combination
    therapy.

23
Inhibitors of DNA Synthesis
Selectivity due to differences between
prokaryotic and eukaryotic enzymes
24
Quinolones (bactericidal)nalidixic acid,
ciprofloxacin, ofloxacin, norfloxacin,
levofloxacin, lomefloxacin, sparfloxacin
  • Mode of action - These antimicrobials bind to the
    A subunit of DNA gyrase (topoisomerase) and
    prevent supercoiling of DNA, thereby inhibiting
    DNA synthesis.
  • Spectrum of activity - Gram-positive cocci and
    urinary tract infections
  • Resistance - Common for nalidixic acid
    developing for ciprofloxacin

25
Antimetabolite Antimicrobials
26
Inhibitors of Folic Acid Synthesis
  • Basis of Selectivity
  • Review of Folic Acid Metabolism

27
Sulfonamides, Sulfones (bacteriostatic)
  • Mode of action - These antimicrobials are
    analogues of para-aminobenzoic acid and
    competitively inhibit formation of dihydropteroic
    acid.
  • Spectrum of activity - Broad range activity
    against gram-positive and gram-negative bacteria
    used primarily in urinary tract and Nocardia
    infections.
  • Resistance - Common
  • Combination therapy - The sulfonamides are used
    in combination with trimethoprim this
    combination blocks two distinct steps in folic
    acid metabolism and prevents the emergence of
    resistant strains.

28
Trimethoprim, Methotrexate, Pyrimethamine
(bacteriostatic)
  • Mode of action - These antimicrobials binds to
    dihydrofolate reductase and inhibit formation of
    tetrahydrofolic acid.
  • Spectrum of activity - Broad range activity
    against gram-positive and gram-negative bacteria
    used primarily in urinary tract and Nocardia
    infections.
  • Resistance - Common
  • Combination therapy - These antimicrobials are
    used in combination with the sulfonamides this
    combination blocks two distinct steps in folic
    acid metabolism and prevents the emergence of
    resistant strains.

29
Anti-Mycobacterial Antibiotics
30
Para-aminosalicylic acid (PSA) (bacteriostatic)
  • Mode of action - Similar to sulfonamides
  • Spectrum of activity - Specific for Mycobacterium
    tuberculosis

31
Dapsone (bacteriostatic)
  • Mode of action - Similar to sulfonamides
  • Spectrum of activity - Used in treatment of
    leprosy (Mycobacterium leprae)

32
Isoniazid (INH) (bacteriostatic )
  • Mode of action - Isoniazid inhibits synthesis of
    mycolic acids.
  • Spectrum of activity - Used in treatment of
    tuberculosis
  • Resistance - Has developed

33
Antimicrobial Drug ResistancePrinciples and
Definitions
  • Clinical resistance
  • Resistance can arise by mutation or by gene
    transfer (e.g. acquisition of a plasmid)
  • Resistance provides a selective advantage
  • Resistance can result from single or multiple
    steps
  • Cross resistance vs multiple resistance
  • Cross resistance -- Single mechanism-- closely
    related antibiotics
  • Multiple resistance -- Multiple mechanisms --
    unrelated antibiotics

34
Antimicrobial Drug ResistanceMechanisms
  • Altered permeability
  • Altered influx
  • Gram negative bacteria
  • Altered efflux
  • tetracycline
  • Inactivation
  • ?-lactamse
  • Chloramphenicol acetyl transferase

35
Antimicrobial Drug ResistanceMechanisms
  • Altered target site
  • Penicillin binding proteins (penicillins)
  • RNA polymerase (rifampin)
  • 30S ribosome (streptomycin)
  • Replacement of a sensitive pathway
  • Acquisition of a resistant enzyme (sulfonamides,
    trimethoprim)
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