03-11-21 - Principles of Antimicrobial Therapy Flashcards
Learning Outcomes
- Define the principles of antibiotic chemotherapy
- List the main classes of antibacterial agents
- Describe the principle of selective toxicity giving examples
- Outline the main mechanisms of action of the main antibiotic classes
What are chemotherapeutic agents used for?
What is central to use of chemotherapeutic agents?
Why is this important?
What does this depend on?
- Chemotherapeutic agents are used to directly or indirectly inhibit uncontrolled growth and proliferation of cancer cells
- Central to the use of chemotherapeutic agents is the concept of selective toxicity
- This is important as these drugs are intended to be toxic to invading organisms or cancerous cells. But relatively harmless to the host or normal cells
- This is dependent on there being biochemical difference between the target cells and the host
What are 3 examples of selective toxicity?
1) Penicillins – In the absence of allergy, there is very low toxicity to the host, meaning very large doses can be used to flush out invading organisms
2) Aminoglycosides have a very narrow therapeutic index, so the toxic dose is very close to the therapeutic dose, meaning great care has to be taken to avoid harm to the host
3) Anti-TB drugs, such as isoniazid and pyrazinamide, may cause certain patient to develop hepatoxicity (toxic build-up in liver). This is due to genetic acetylation rates, where slow acetylation results in build-up in the liver, which may result in treatment being stopped
What are peptidoglycans?
What are these strands made up of?
What gives the bacterial cell wall its strength?
- Bacterial cell walls are made up of various strands of peptidoglycans, which are not present in eukaryotes
- The strands are made up of multiple amino sugars such as N-Acetylglucosamine (NAG) and N-Acetylmuramic Acid (NAMA)
- NAM has a short peptide side chain, which can cross link to form a lattice work of a strong elastic macromolecule
- This cross-linking gives the cell all its strength
Table of anti-biotics against the cell membrane
What do Beta-lactams function?
What does this lead to?
What reaction is this?
- Beta-lactams prevent the cross-linking between the short peptide side chains of NAMA, meaning peptide cross-links cannot occur
- This results in the bacterial cells losing all its strength and being killed
- This is known as a bactericidal anti-biotic, as the bacterial cell is killed
6) How do the following antibiotic function in the bacterial cell: • Cyloserine • Bacitracin • Vancomycin • Β-lactams
- Cyloserine functions inside the bacterial cells
- Bacitracin functions in the cell membrane
- Vancomycin and Beta-lactams function outside the cell on the cell wall
What are the 4 different kinds of penicllin?
What are the examples in each section?
1) Naturally occurring penicillin
• Penicillin G
• Penicillin V (derived from penicillin G)
2) B-lactamase resistant penicillin • Beta lactamase is an enzyme that can break down the beta lactam ring that is central to the core of beta-lactam anti-biotics • Dicloxacillin • Cloxacillin • Methicillin • Nafcillin • Oxacillin
3) Broad-spectrum penicillins
• Wide range of activity
• Ampicillin
• Amoxicillin
4) Extended-spectrum pencillins • Can be used on a wide range of organisms for long periods of time • Very effective • MRSA (methicillin resistant staphylococcus aureus) and ESBL (extended-spectrum beta lactamase) can break down all of these penicillins • Azlocillin • Carbenicillin • Piperacillin • Ticarcillin
Where do cephalosporins come from?
How do they function?
How are they classified?
How can they be termed?
- Cephalosporins come from the fungus cephalosporins
- They function similarly to peniclillins
- Cephalosporins are classified by generations in the order which they were developed e.g 1st, 2nd, 3rd
- They can be termed by means of administration:
- Oral is cephalexin
- Parenteral (any non-oral means) are cefuroxime and cefotaxime
How do bacterial folate antagonists work?
How is this a good example of selective toxicity?
What are examples of Bacterial folate antagonists?
What are these an example of?
- Bacterial folate protagonists act through an inhibition of the folate pathway in bacteria
- Folate is very important in cell metabolism, but folate systems are not present in humans, we get it from our diet
- This makes bacteria very susceptible to this anti-biotics, as without folate, they won’t be able to grow, but makes it safe for humans
• Examples of bacterial folate antagonists are:
1) Sulphonamides
2) Trimethoprim
• These are examples of bacteriostatic anti-biotics, as they prevent bacterial growth by interfering with DNA replication and other aspects of cellular metabolism
How do aminoglycoside antibiotics work?
What 2 ways do they bind to ribosomes?
How do they inhibit protein synthesis?
What are 4 examples of aminoglycosides?
What type of anti-biotics are these?
- Aminoglycosides form ionic bonds at the bacterial cell surface
- They then penetrate the cell wall by being actively taken up through transport mechanisms across the cell membrane
- They can then diffuse into the cytoplasm and bind to bacterial ribosomes in order to inhibit protein synthesis
- Aminoglycosides binds irreversibly to ribosomes at the interface between the assembled 30s and 50s subunits.
- This prevents the binding of Trna to the 30s subunit, meaning protein synthesis cant be started, as trna cant bring the amino acids required
- Amino glycosides can also bind directly to the individual subunits of ribosomes
- Aminoglycosides inhibit protein synthesis by causing the misreading of mRNA
• Examples of aminoglycosides:
1) Streptomycin
2) Kanamycin
3) Neomycin
4) Gentamicin
• These anti-biotics are bactericidal, as they cause the death of the cells
What do tetracyclines prevent?
How does this affect the peptide chain in bacterial cell walls?
What causes the differences in the activity of tetracyclines?
What 2 ways do tetracyclines differ from aminoglycosides?
- Tetracyclines prevent the attachment of Trna to the acceptor site on the Mrna ribosomal complex
- This prevents the addition of amino acids to the peptide chain
- The differences in activity of the individual tetracyclines are related to their solubility in the lipid membrane of bacteria
- Tetracyclines can diffuse through the bacterial cell membrane, whereas aminoglycosides have to be actively taken up
- Tetracyclines bind weakly to ribosomes, whereas aminoglycoside binding to ribosomes is irreversible
What is unique about Chloramphenicol?
What do Chloramphenicol, erythromycin and Clindamycin do?
How do they do this?
What is the additional function of erythromycin?
- Chloramphenicol is a miscellaneous agent, meaning they don’t belong to a class of anti-biotics
- These 3 anti-biotics prevent the addition of new amino acids to the growing peptide chains
- They bind to ribosomes, which prevents the association of peptidyl-transferase with amino acids, meaning no peptide bond can be formed
- Erythromycin can also prevent translocation of the ribosome down an Mrna template, meaning protein synthesis can’t occur
What are fluoroquinolones?
What are 3 examples of broad-spectrum agents?
What is an example of a narrow-spectrum agent?
How do fluroquinolones work?
What 2 things are fluoroquinolones defined by?
Why are fluoroquinolones limited?
- Fluoroquinolones are synthetic antibiotics
- 3 broad spectrum agents:
1) Ciprofloxacin
2) Ofloxacin
3) Norfloxacin
• Narrow spectrum agents:
1) Nalidixic acid (not fluorinated)
- Fluoroquinolones work by inhibiting bacterial DNA Gyrase
- This enzyme catalyses the introduction of the negative supercoil in DNA, which is needed to permit transcription and DNA replication
- DNA is folded for being read and supercoiled for being stored
- If it cant be folded, it cant be read, if it cant be supercoiled, it gets in the way of other areas of the cell, leading to the cell not being able to function
• Fluoroquinolones are defined by:
1) Spectrum of activity ie which organism they will kill
2) Pharmacokinetics – study of time course of drug absorption, distribution, excretion etc
- Fluoroquinolones are often limited because of their broad spectrum
- Treatment can impact the normal microbiota found in and around the body
