Title: Antimicrobial Agents
1Antimicrobial Agents
- Mechanisms of Action and Spectra
- of Activity
2OBJECTIVES
- Describe major classes of antimicrobials and
their mechanisms of action - Know the spectra of activity of commonly used
antibiotics - Understand the mechanisms of resistance to
antibiotics - Know the principle and rationale behind
antibiotic susceptibility testing
3Overview 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
4Spectrum of Activity
- Broad Spectrum Antibiotics
- Effective against many types
- Example Tetracycline
- Narrow Spectrum Antibiotics
- Effective against very few types
- Example Penicillin
5Bactericidal v. Bacteriostatic
- Bactericidal
- Kill bacteria
- Used when the host defense mechanisms are
impaired - Required in endocarditis, kidney infection
- Bacteriostatic
- Inhibit bacteria
- Used when the host defense mechanisms are intact
- Used in many infectious diseases
6MECHANISMS OF ACTION OF MAJOR GROUPS OF
ANTIBIOTICS
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8STRUCTURE OF ?-LACTAM ANTIBIOTICS
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10PENICILLIN HOME
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12Penicillin Home
- Looks like a house with a new room added to the
side - Think of the R-group as of a funky antenna
- Changing antennae and or finishing the
basement will create better homes
(penicillins)
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14Penicillin 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
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17SPECTRUM OF ACTIVITY OF CEPHALOSPORINS
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19MECHANISM OF ACTION OF ?-LACTAM ANTIBIOTICS
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21?-lactam antibiotics are ineffective against
protoplasts and spheroplastsA. TRUEB. FALSE
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23MECHANISMS OF ACTION OF ANTIRIBOSOMAL ANTIBIOTICS
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25Inhibition 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
26Ribosome Home Plate
- Baseball player slides into home
- The ball is fielded by the catcher who makes a
CLEan TAG - The word CLEean lies over the base these inhibit
? 50S - The word TAG lies beneath the base these inhibit
30S
27 How are these drugs administered?
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29MECHANISM OF ACTION OF SULFONAMIDES AND
TRIMETHOPRIM
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31Mechanisms of Resistance
- Genetic Mechanisms
- Non-Genetic Mechanisms
32Genetic 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
33Non-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)
34The End Result of Genetically Conferred Resistance
- Production of drug-inactivating enzymes
- Modification of target structures
- Alteration of membrane permeability
35Resistance to Beta-Lactams
- Gram
- ?-lactamase (Penicillinase)
- Alteration of the transpeptidase enzyme
- Gram -
- ?-Lactamase (Penicillinase)
- Alteration of porins
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38How can we test for susceptibility/resistance
?
39Antibiotic Susceptibility Testing
- Dilution Method
- Disc Diffusion Method
- E-test
- High-Tech Methods
40Dilution 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)
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42Disc 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
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45 Therapeutic Index Max. Safely
Achievable Level MIC
46Take Home Message
- Antibiotic Targets
- Bactericidal v. Bacteriostatic Drugs
- Spectrum of Activity
- Major Groups of Drugs
- Mechanisms of Resistance
- Susceptibility Tests