Академический Документы
Профессиональный Документы
Культура Документы
Dr. Buckhaults
Antibiotics Disrupt Cell Wall Synthesis, Protein
Synthesis, Nucleic Acid Synthesis and Metabolism
Principles and Definitions
• Selectivity
– Selectivityvstoxicity
• Therapeutic index
– Toxic dose/ Effective dose
• Categories of antibiotics
– Bacteriostatic
• Reversibly inhibit growth
• Duration of treatment sufficient for host defenses to eradicate
infection
– Bactericidal-
• Kill bacteria
• Usually antibiotic of choice for infections in sites such as
endocardium or the meninges where host defenses are ineffective.
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 to immediately block
synthesis of toxin.
Principles and Definitions
• Antibiotic susceptibility testing (in vitro)
– Bacteriostatic Antibiotics
• Minimum inhibitory concentration (MIC)
• Lowest concentration that results in inhibition of visible growth
(colonies on a plate or turbidity of liquid culture)
– Bactericidal Antibiotics
• Minimum bactericidal concentration (MBC)
• Lowest concentration that kills 99.9% of the original inoculum
Antibiotic Susceptibility Testing-MIC
Disk Diffusion Test
Determination of MIC
Str
Tet Ery
8 4 2 1 0 Chl Amp
Tetracycline (g/ml)
MIC = 2 g/ml
•Inhibitors of INITATION
•30S Ribosomal Subunit (Aminoglycosides, Tetracyclines, Spectinomycin)
•50S Ribosomal Subunit (Chloramphenicol, Macrolides)
•Inhibitors of ELONGATION
•Elongation Factor G (Fusidic acid)
Review of Initiation of Protein Synthesis
1 3
30S 2 GTP
1 2 3 GTP
Initiation Factors
f-met-tRNA
mRNA
Spectinomycin
GDP + Pi
2
50S
P A
1 1
2 GTP
70S Aminoglycosides
30S
Initiation Initiation
Complex Complex
Review of Elongation of Protein Synthesis
P A Tetracycline P A
Tu GTP Tu GDP + Pi
GTP Ts
Ts Tu
Ts GDP
Chloramphenicol
GDP
Fusidic Acid +
GTP
G
G GDP + Pi
G GTP
P A P A
Erythromycin
Survey of Antibiotics
• Mostly bacteriostatic
• Selectivity due to differences in prokaryotic
and eukaryotic ribosomes
• Some toxicity - 70S ribosomes eukaryotic
in mitochondria
Antimicrobials that Bind to the 30S
Ribosomal Subunit
QuickTimeª and a
TIFF (Uncompressed) decompressor
are needed to see this picture. Aminoglycosides
(only bactericidal protein synthesis inhibitor)
streptomycin, kanamycin, gentamicin, tobramycin,
amikacin, netilmicin, neomycin (topical)
• Modes of action -
– Irreversibly bind to the 16S ribosomal RNA and freeze the 30S
initiation complex (30S-mRNA-tRNA) and prevents initiation
of translation.
– Increase the affinity of the A site for t-RNA regardless of the
anticodon specificity. Induces misreading of the mRNA for
proteins already being synthesized.
– Destabilize microbial membranes
– Multiple modes of action is the reason this protein synthesis
inhibitor is bactericidal.
Aminoglycosides (bactericidal)
streptomycin, kanamycin, gentamicin, tobramycin,
amikacin, netilmicin, neomycin (topical)
Tetracyclines (bacteriostatic)
are needed to see this picture.
• Resistance - Common
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. Does not
destabilize membranes, and is therefore bacteriostatic
• Resistance - Common
Macrolides (bacteriostatic)
erythromycin, clarithromycin, azithromycin, spiramycin
• Resistance - Common
Antimicrobials that Interfere with
Elongation Factors
Selectivity due to differences in prokaryotic and eukaryotic
elongation factors
QuickTimeª and a
TIFF (Uncompressed) decompressor
are needed to see this picture.
(bactericidal)
• Mode of action - These antimicrobials bind to DNA-dependent RNA
polymerase and inhibit initiation of mRNA synthesis.
Dihydropteroic acid
Dihydrofolate
synthetase
Dihydrofolic acid
Dihydrofolate
Trimethoprim reductase
Tetrahydrofolic acid
Thymidine Methionine
Purines
QuickTimeª and a
TIFF (Uncompressed) decompressor
are needed to see this picture.
Sulfonamides,
Sulfones
(bacteriostatic)
• Mode of action - These antimicrobials are analogues of para-
aminobenzoic acid and competitively inhibit pteridine synthetase, block
the formation of dihydropteroic acid.
• Resistance - Common
• Resistance - Common
– Altered efflux
• Acquire transporter gene that will pump the antibiotic out (Tetracycline)
Antimicrobial Drug Resistance
Mechanisms
• Inactivation of the antibiotic
β -lactamase
Chloramphenicol Acetyl Transferase
Antimicrobial Drug Resistance
Mechanisms