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Published on December 5, 2007

Author: lebahiep

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Antibiotics: Protein Synthesis, Nucleic Acid Synthesis and Metabolism

Principles and Definitions Selectivity Selectivty   toxicity  Therapeutic index Toxic dose/ Effective dose Categories of antibiotics Bacteriostatic Duration of treatment sufficient for host defenses Bactericidal Usually antibiotic of choice

Selectivity

Selectivty   toxicity 

Therapeutic index

Toxic dose/ Effective dose

Categories of antibiotics

Bacteriostatic

Duration of treatment sufficient for host defenses

Bactericidal

Usually antibiotic of choice

Principles and Definitions Selectivity Therapeutic index Categories of antibiotics Use of bacteriostatic vs bactericidal antibiotic Therapeutic index better for bacteriostatic antibiotic Resistance to bactericidal antibiotic Protein toxin mediates disease – use bacteriostatic protein synthesis inhibitor

Selectivity

Therapeutic index

Categories of antibiotics

Use of bacteriostatic vs bactericidal antibiotic

Therapeutic index better for bacteriostatic antibiotic

Resistance to bactericidal antibiotic

Protein toxin mediates disease – use bacteriostatic protein synthesis inhibitor

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 (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 8 4 0 2 1 Tetracycline (  g/ml) MIC = 2  g/ml Determination of MIC Chl Amp Ery Str Tet Disk Diffusion Test

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

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

Antibiotics that Inhibit Protein Synthesis

Review of Initiation of Protein Synthesis 30S 1 3 2 GTP 1 2 3 GTP Initiation Factors mRNA 3 1 2 GTP 30S Initiation Complex f-met-tRNA Spectinomycin Aminoglycosides 1 2 GDP + Pi 50S 70S Initiation Complex A P

Review of Elongation of Protein Synthesis GTP A P Tu GTP Tu GDP Ts Ts Tu + GDP Ts Pi P A Tetracycline A P Erythromycin Fusidic Acid Chloramphenicol G GTP G GDP + Pi G GDP A P + GTP

Protein Synthesis Microbe Library -American Society for Microbiology www.microbelibrary.org

Survey of Antibiotics

Protein Synthesis Inhibitors Mostly bacteriostatic Selectivity due to differences in prokaryotic and eukaryotic ribosomes Some toxicity - eukaryotic 70S ribosomes

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.

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.

Microbe Library American Society for Microbiology www.microbelibrary.org

Aminoglycosides (bactericidal) streptomycin , kanamycin, gentamicin, tobramycin, amikacin, netilmicin, neomycin (topical) 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.

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.

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

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.

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

Mode of action - The macrolides inhibit translocation.

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

Resistance - Common

Microbe Library American Society for Microbiology www.microbelibrary.org

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

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 - Broad 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.

Mode of action - These antimicrobials bind to DNA-dependent RNA polymerase and inhibit initiation of mRNA synthesis.

Spectrum of activity - Broad 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

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

Inhibitors of Folic Acid Synthesis Basis of Selectivity Review of Folic Acid Metabolism p-aminobenzoic acid + Pteridine Dihydropteroic acid Dihydrofolic acid Tetrahydrofolic acid Pteridine synthetase Dihydrofolate synthetase Dihydrofolate reductase Thymidine Purines Methionine Trimethoprim Sulfonamides

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.

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.

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

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 )

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

Mode of action - Isoniazid inhibits synthesis of mycolic acids.

Spectrum of activity - Used in treatment of tuberculosis

Resistance - Has developed

Antimicrobial Drug Resistance Principles and Definitions Clinical resistance vs actual 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

Clinical resistance vs actual 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 Resistance Mechanisms Altered permeability Altered influx Gram negative bacteria

Altered permeability

Altered influx

Gram negative bacteria

Microbe Library American Society for Microbiology www.microbelibrary.org

Antimicrobial Drug Resistance Mechanisms Altered permeability Altered efflux tetracycline Microbe Library American Society for Microbiology www.microbelibrary.org

Altered permeability

Altered efflux

tetracycline

Antimicrobial Drug Resistance Mechanisms Inactivation  -lactamase Chloramphenicol acetyl transferase Microbe Library American Society for Microbiology www.microbelibrary.org

Inactivation

 -lactamase

Chloramphenicol acetyl transferase

Antimicrobial Drug Resistance Mechanisms Altered target site Penicillin binding proteins (penicillins) RNA polymerase (rifampin) 30S ribosome (streptomycin) Microbe Library American Society for Microbiology www.microbelibrary.org

Altered target site

Penicillin binding proteins (penicillins)

RNA polymerase (rifampin)

30S ribosome (streptomycin)

Antimicrobial Drug Resistance Mechanisms Replacement of a sensitive pathway Acquisition of a resistant enzyme (sulfonamides, trimethoprim)

Replacement of a sensitive pathway

Acquisition of a resistant enzyme (sulfonamides, trimethoprim)

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