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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

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Antibiotics: Protein Synthesis, Nucleic Acid Synthesis and Metabolism


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


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


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


Zone Diameter Standards for Disk Diffusion Tests


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


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


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


Survey of Antibiotics


Protein Synthesis Inhibitors

  • Mostly bacteriostatic

  • Selectivity due to differences in prokaryotic and eukaryotic ribosomes

  • Some toxicity - eukaryotic 70S ribosomes


Antimicrobials that Bind to the 30S Ribosomal Subunit


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.


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.


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


Antimicrobials that Bind to the 50S Ribosomal Subunit


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.


Macrolides (bacteriostatic)erythromycin, clarithromycin, azithromycin, spiramycin

  • Mode of action - The macrolides inhibit translocation.

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

  • Resistance - Common


Antimicrobials that Interfere with Elongation Factors

Selectivity due to differences in prokaryotic and eukaryotic

elongation factors


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


Inhibitors of Nucleic Acid Synthesis


Inhibitors of RNA Synthesis

Selectivity due to differences between prokaryotic and eukaryotic

RNA polymerase


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.


Inhibitors of DNA Synthesis

Selectivity due to differences between prokaryotic and eukaryotic enzymes


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


Antimetabolite Antimicrobials


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


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.


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.


Anti-Mycobacterial Antibiotics


Para-aminosalicylic acid (PSA)(bacteriostatic)

  • Mode of action - Similar to sulfonamides

  • Spectrum of activity - Specific for Mycobacterium tuberculosis


Dapsone(bacteriostatic)

  • Mode of action - Similar to sulfonamides

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


Isoniazid (INH)(bacteriostatic )

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

  • Spectrum of activity - Used in treatment of tuberculosis

  • Resistance - Has developed


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


Antimicrobial Drug ResistanceMechanisms

  • Altered permeability

    • Altered influx

      • Gram negative bacteria

    • Altered efflux

      • tetracycline

  • Inactivation

    • -lactamse

    • Chloramphenicol acetyl transferase


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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