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Antibiotics: Protein Synthesis, Nucleic Acid Synthesis and Metabolism. Principles and Definitions. Selectivity Selectivty 8 toxicity 9 Therapeutic index Toxic dose/ Effective dose Categories of antibiotics Bactericidal Usually antibiotic of choice Bacteriostatic

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Antibiotics protein synthesis nucleic acid synthesis and metabolism l.jpg

Antibiotics: Protein Synthesis, Nucleic Acid Synthesis and Metabolism


Principles and definitions l.jpg

Principles and Definitions

  • Selectivity

    • Selectivty8toxicity9

  • Therapeutic index

    • Toxic dose/ Effective dose

  • Categories of antibiotics

    • Bactericidal

      • Usually antibiotic of choice

    • Bacteriostatic

      • Duration of treatment sufficient for host defenses


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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


Antibiotic susceptibility testing l.jpg

Disk Diffusion Test

Determination of MIC

Str

Tet

Ery

4

2

1

0

8

Tetracycline (g/ml)

Chl

Amp

MIC = 2 g/ml

Antibiotic Susceptibility Testing


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Zone Diameter Standards for Disk Diffusion Tests


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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


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3

1

GTP

2

30S

GTP

1

2

3

Initiation Factors

f-met-tRNA

mRNA

Spectinomycin

3

50S

GDP + Pi

GTP

2

2

P

A

1

1

Aminoglycosides

70S Initiation Complex

30S Initiation Complex

Review of Initiation of Protein Synthesis


Review of elongation of protein synthesis l.jpg

Tetracycline

P

A

P

A

+

Tu

Tu

GTP

Pi

GDP

Ts

GTP

Tu

Ts

Ts

Chloramphenicol

GDP

GDP

+

Fusidic Acid

GTP

G

G

G

P

A

GTP

GDP

+

Pi

P

A

Erythromycin

Review of Elongation of Protein Synthesis


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Survey of Antibiotics


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Protein Synthesis Inhibitors

  • Mostly bacteriostatic

  • Selectivity due to differences in prokaryotic and eukaryotic ribosomes

  • Some toxicity - eukaryotic 70S ribosomes


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Antimicrobials that Bind to the 30S Ribosomal Subunit


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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.


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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.


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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


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Antimicrobials that Bind to the 50S Ribosomal Subunit


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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.


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Macrolides (bacteriostatic)erythromycin, clarithromycin, azithromycin, spiramycin

  • Mode of action - The macrolides inhibit translocation.

  • Spectrum of activity - Gram-positive bacteria, Mycoplasma, Legionella

  • Resistance - Common


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Antimicrobials that Interfere with Elongation Factors

Selectivity due to differences in prokaryotic and eukaryotic

elongation factors


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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


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Inhibitors of Nucleic Acid Synthesis


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Inhibitors of RNA Synthesis

Selectivity due to differences between prokaryotic and eukaryotic

RNA polymerase


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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.


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Inhibitors of DNA Synthesis

Selectivity due to differences between prokaryotic and eukaryotic enzymes


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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


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Antimetabolite Antimicrobials


Inhibitors of folic acid synthesis l.jpg

Sulfonamides

p-aminobenzoic acid + Pteridine

Pteridine synthetase

Dihydropteroic acid

Dihydrofolate synthetase

Dihydrofolic acid

Dihydrofolate reductase

Trimethoprim

Tetrahydrofolic acid

Methionine

Thymidine

Purines

Inhibitors of Folic Acid Synthesis

  • Basis of Selectivity

  • Review of Folic Acid Metabolism


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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.


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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.


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Anti-Mycobacterial Antibiotics


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Para-aminosalicylic acid (PSA)(bacteriostatic)

  • Mode of action - Similar to sulfonamides

  • Spectrum of activity - Specific for Mycobacterium tuberculosis


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Dapsone(bacteriostatic)

  • Mode of action - Similar to sulfonamides

  • Spectrum of activity - Used in treatment of leprosy (Mycobacterium leprae)


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Isoniazid (INH)(bacteriostatic )

  • Mode of action - Isoniazid inhibits synthesis of mycolic acids.

  • Spectrum of activity - Used in treatment of tuberculosis

  • Resistance - Has developed


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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


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Antimicrobial Drug ResistanceMechanisms

  • Altered permeability

    • Altered influx

      • Gram negative bacteria

    • Altered efflux

      • tetracycline

  • Inactivation

    • -lactamse

    • Chloramphenicol acetyl transferase


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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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