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Antibiotics
Molecular targets
Principles and Definitions
• Selectivity
– Selectivity vs toxicity
• 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 (mg/ml)
MIC = 2 mg/ml
•Inhibitors of ELONGATION
•Elongation Factor G (Fusidic acid)
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
Elongation of Protein Synthesis
P A Tetracycline P A
Tu GTP Tu GDP + Pi
GTP Ts
Ts Tu
Ts GDP
Chloramphenicol
GDP
+
Fusidic Acid G
GTP
G GDP + Pi
G GTP
P A P A
Erythromycin
Survey of Antibiotics
• Resistance - Common
• Resistance - Common
• Resistance - Common
Antimicrobials that Interfere with
Elongation Factors
Selectivity due to differences in prokaryotic and eukaryotic
elongation factors
Fusidic acid (bacteriostatic)
Tetrahydrofolic acid
Thymidine Methionine
Purines
Sulfonamides, Sulfones
(bacteriostatic)
• Resistance - Common
• Resistance - Common
– Altered efflux
• Acquire transporter gene that will pump the antibiotic out
(Tetracycline)
Antimicrobial Drug Resistance
Mechanisms
• Inactivation of the antibiotic
b-lactamase
Chloramphenicol Acetyl Transferase
Antimicrobial Drug Resistance
Mechanisms
• Mutation in the target site.
– Penicillin binding proteins (penicillins)
– RNA polymerase (rifampin)
– 30S ribosome (streptomycin)
Antimicrobial Drug Resistance
Mechanisms