Week 11 - Antibacterial Chemotherapy Flashcards
Chemotherapeutic Agents
Chemical agents used to treat disease
Destroy pathogenic microbes or inhibit their growth within host
What is selective toxicity?
Ability of drug to kill or inhibit pathogen while damaging host as little as possible
Therapeutic dose, Toxic dose and the Therapeutic Index
Therapeutic dose - drug level required for clinical treatment
Toxic dose - drug level at which drug becomes too toxic for patient
Therapeutic Index = Toxic dose/Therapeutic dose
Must be >1
A low TI means bad for bacteria but also very bad for the host
Properties of Antibacterial Drugs
Cidal - kills
Static - inhibits growth
Broad spectrum drugs - attack many different pathogens
Narrow spectrum drugs - attack only a few different pathogens
How to determine the level of antimicrobial activity?
Can be expressed in 2 ways:
1. Minimal inhibitory concentration (MIC)
- lowest concentration of drug that inhibits growth of a particular pathogen
2. Minimal lethal concentration (MLC)
- lowest concentration of drug that kills pathogen
Techniques usually used:
1. Dilution susceptibility tests for MIC
2. Disk diffusion tests
3. E-test MIC and diffusion
Dilution Susceptibility Tests
Involves inoculating media containing different concentrations of drug
- broth or agar with lowest concentration showing no growth is MIC
Disk Diffusion Tests
Disks impregnated with specific drugs then placed on agar inoculated with test microbe
Drug diffuses from disk to agar establishing concentration gradient
Observe clear zones around disks
E-Test
Similar to disk diffusion method but uses strips rather than disk
Strips contain gradient of an antibiotic
Intersection of elliptical zone of inhibition (clearing) with strip indicates MIC
Convenient for use with aerobic pathogens
Factors Influencing the Effectiveness of Antimicrobial Drugs
- Ability of drug to reach site of infection
- depends on mode of transmission
- e.g. oral, some drugs destroyed by stomach acid - Susceptibility of pathogen to drug
- Ability of drug to reach concentrations in body that exceed MIC of pathogen
- amount administered
- speed of uptake
- route of administration
- rate of clearance from body
Mechanisms of Antibacterial Drug Action
- Inhibition of cell wall synthesis
- Inhibition of protein synthesis
- Inhibition of nucleic acid synthesis
- Metabolic antagonism
Cell Wall Synthesis Inhibition
Inhibit normal synthesis of peptidoglycan by bacteria and cause osmotic lysis
Cell Wall Synthesis Inhibitors
Penicillins and Cephalosporins
- block enzyme that catalyses transpeptidation
- prevents cross linking sugar chains
- prevents synthesis of complete cell walls resulting in weak cell wall and lysis of cell
Vancomycin and Teicoplanin
- glycopeptide antibiotics
- inhibit cell wall synthesis by binding directly to cell wall peptides and blocking transpeptidase enzymes from cross linking sugar chains
Protein Synthesis Inhibition
Alter bacterial ribosomes interfering with translation causing faulty protein synthesis
Many antibiotics bind specifically to bacterial ribosome
- at the 30S (small) or 50S (large) subunits
Other antibiotics inhibit a step in protein synthesis
- mRNA reading
- peptide bond formation etc.
Molecules that Inhibit Protein Synthesis
Aminoglycosides
- bind irreversibly to 30S subunit of ribosome
- prevents 50S subunit from attaching translation initiation complex
- causes misreading of codons
Tetracyclines
- bind irreversibly to 30S subunit leading to distortion and misalignment of tRNA and mRNA
Chloramphenicol
- bacteriostatic
- binds to 50S subunit
- inhibits petidyl transferase
Erythromycin and other Macrolides
- bacteriostatic
- binds to 50S subunit
- Inhibits peptide chain elongation during protein synthesis so no new proteins can be made
Nucleic Acid Synthesis Inhibition
Can block DNA replication
- inhibition of DNA polymerase and DNA helicase
Block transcription
- inhibition of RNA polymerase
