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Antimicrobial AgentsMohammad Reza Fazeli, PharmD, PhD
Professor of Microbiology
Department of Drug and Food Control
Faculty of Pharmacy
Tehran University of Medical Sciences
Overview of Antibiotics as Therapeutic Agents Selective Inhibition/Toxicity
• Due to the differences in structure and metabolic pathways
• Harm microorganisms, not the host Four major sites:
• Cell wall• Ribosomes• DNA• Cell membrane
Spectrum of Activity
Broad Spectrum Antibiotics:• Effective against many types
• Example: Tetracycline
Narrow Spectrum Antibiotics:• Effective against very few types
• Example: Penicillin
Bactericidal v. Bacteriostatic
Bactericidal:
• Kill bacteria
• Used when the host defense mechanisms are impaired
Bacteriostatic:
• Inhibit bacteria
• Used when the host defense mechanisms are intact
MECHANISMS OF ACTION OF MAJOR GROUPS OF ANTIBIOTICS
STRUCTURE OF -LACTAM ANTIBIOTICS
PENICILLIN HOME
“Penicillin Home”
Looks like a house with a new room added to the side
Think of the R-group as of an antenna Changing “antennae” and or finishing the
“basement” will create better “homes” (penicillins)
[Penicillin] Home Improvement Project Adding a new antenna creates broad
spectrum penicillins • Example: Ampicillin
Adding additional antennae and finishing the basement creates cephalosporins• Example: 1st, 2nd, 3rd, & 4th generation
cephalosporins
SPECTRUM OF ACTIVITY OF CEPHALOSPORINS
MECHANISM OF ACTION OF -LACTAM ANTIBIOTICS
β-Lactam antibiotics inhibit the formation of peptidoglycan cross-links in the bacterial cell wall, but have no direct effect on cell wall degradation
The β-lactam moiety of penicillin binds to the enzyme (transpeptidase) that links the peptidoglycan molecules in bacteria. The enzymes that hydrolyze the peptidoglycan cross-links continue to function, which weakens the cell wall of the bacterium
Bacteria constantly remodel their peptidoglycan cell walls, simultaneously building and breaking down portions of the cell wall as they grow and divide
Gram-positive bacteria are called protoplasts when they lose their cell walls. Gram-negative bacteria do not lose their cell walls completely and are called spheroplasts after treatment with penicillin
-lactam antibiotics are ineffective against protoplasts and spheroplasts:
MECHANISMS OF ACTION OF ANTIRIBOSOMAL ANTIBIOTICS
Inhibition of Protein Synthesis
Anti-ribosomal antibiotics impair ribosomes by binding to either 50S or 30S ribosomal subunits
Ribosomes are essential for translation of mRNA into proteins
No translation No protein synthesis No protein synthesis No growth
MECHANISM OF ACTION OF SULFONAMIDES AND TRIMETHOPRIM
Folic acid (also known as folate , vitamin M, vitamin B9, vitamin Bc or folacin are forms of the water-soluble vitamin B9.
Folic acid is itself not biologically active, but its biological importance is due to tetrahydrofolate and other derivatives after its conversion to dihydrofolic acid in the liver.
Vitamin B9 (folic acid and folate) is essential for numerous body functions. The human body needs folate to synthesize DNA, repair DNA, and methylate DNA as well as to act as a cofactor in certain biological reactions. It is especially important in aiding rapid cell division and growth, such as in infancy and pregnancy. Children and adults both require folic acid to produce healthy red blood cells and prevent anemia.
Mechanisms of Resistance
Genetic Mechanisms
Non-Genetic Mechanisms
Genetic Mechanisms Chromosome-mediated
• Due to spontaneous mutation: • in the target molecule • in the drug uptake system
Plasmid-mediated• Common in Gram-negative rods• Transferred via conjugation• Multidrug resistance
Transposon-mediated
Non-Genetic Mechanism
Inaccessibility to drugs (e.g., abscess, TB lesion)
Stationary phase (insusceptible to inhibitors of cell wall synthesis)
Protoplasts and spheroplasts (insusceptible to inhibitors of cell wall synthesis)
The End Result of Genetically Conferred Resistance
Production of drug-inactivating enzymes
Modification of target structures
Alteration of membrane permeability
Resistance to Beta-Lactams
Gram +
-lactamase (Penicillinase)
• Alteration of the transpeptidase enzyme
Gram -
-Lactamase (Penicillinase)
• Alteration of porins
How can we test for susceptibility/resistance?
Antibiotic Susceptibility Testing
Dilution Method
Disc Diffusion Method
E-test
High-Tech Methods
Dilution Method
Prepare two fold [antibiotic] dilutions Add 1/2 a million bacterial cells per tube Incubate overnight Check for turbidity Establish the MIC:
• The lowest concentration of the drug that prevented the bacterial growth (no turbidity)
Disc Diffusion Method
Seed agar plates with bacteria in question Place antibiotic-discs over the seeded plate Incubate overnight Measure the inhibition zones Relate the results to the zones given in the
interpretive chart There is an inverse relationship between the
MICs and zone diameters
Therapeutic Index =
Max. Safely Achievable Level MIC