03-11-21 - Principles of Antimicrobial Therapy

Question 1

What are chemotherapeutic agents used for?

What is central to use of chemotherapeutic agents?

Why is this important?

What does this depend on?

Answer 1

• 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

Question 2

What are 3 examples of selective toxicity?

Answer 2

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

1. Penicillins
   Very low toxicity to the host (if no allergy): Penicillin is one of the safest antibiotics available. It has a wide therapeutic index, which means that the range between the dose that is effective in killing bacteria and the dose that could be harmful to the person is very large. This allows healthcare providers to use high doses of penicillin when necessary to treat serious infections without posing significant risk to the patient.
   “Flushing out invading organisms”: Because penicillin is so safe and effective, large doses can be used to target and kill bacteria without causing harm to the person (unless they are allergic to it).
2. Aminoglycosides
   Narrow therapeutic index: Aminoglycosides (e.g., gentamicin, amikacin) are potent antibiotics but have a narrow therapeutic index, meaning that the difference between a therapeutic dose (the dose that is effective for treating an infection) and the toxic dose (the dose that can cause harm) is very small.
   Risk of toxicity: Because of this narrow margin, aminoglycosides are more likely to cause side effects like nephrotoxicity (kidney damage) or ototoxicity (hearing or balance problems) if the dose is too high. Careful monitoring of drug levels in the blood is necessary to prevent these toxic effects, and doctors must be very precise with dosing.
3. Anti-TB Drugs (Isoniazid and Pyrazinamide)
   Hepatotoxicity risk: Both isoniazid and pyrazinamide are used to treat tuberculosis (TB), but they can cause hepatotoxicity (liver damage). This risk is more pronounced in certain patients.
   Slow acetylators: The body’s ability to process (metabolize) these drugs depends on genetic factors. People who are slow acetylators metabolize these drugs more slowly, leading to drug accumulation in the liver. This build-up can overwhelm the liver, causing damage (hepatotoxicity). If this happens, treatment may need to be stopped to prevent further liver harm.

Question 3

Where are peptidoglycans?

What are these strands made up of? NAG NAMA

What gives the bacterial cell wall its strength?

Answer 3

• 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

Question 4

Table of anti-biotics against the cell membrane
-target - mechanisms - examples

Answer 4

Here’s the information from the table, reorganized and summarized in note form:

Antibiotics and Their Mechanisms of Action

1. Beta-lactam and Cephalosporin
   
   • Target: Penicillin-binding proteins.
   • Mechanism:
     
     • Prevents peptidoglycan cross-linking.
     • Inhibits bacterial cell wall formation by disrupting lattice structure.
   • Examples:
     
     • Penicillin G
     • Flucloxacillin
     • Tazobactam

2. Glycopeptides
   
   • Target: C-terminal D-Ala-D-Ala of the peptidoglycan precursor.
   • Mechanism:
     
     • Prevents transglycosylation and transpeptidation.
     • Blocks addition of glycan peptides to the growing chain (prevents proper cell wall assembly).
   • Examples:
     
     • Vancomycin
     • Teicoplanin

3. Cyclic Peptides
   
   • Target: C55-isopropyl pyrophosphate.
   • Mechanism:
     
     • Inhibits the carriage of building blocks (precursors) for peptidoglycan outside the bacterial inner membrane.
   • Examples:
     
     • Bacitracin
     • Polymyxin

4. Phosphonic Acids
   
   • Target: MurA protein.
   • Mechanism:
     
     • Inhibits the first stage of peptidoglycan synthesis.
   • Examples:
     
     • Fosfomycin

5. Lipopeptides
   
   • Target: Cell wall stress stimulus.
   • Mechanism:
     
     • Induces calcium-dependent membrane depolarization.
     • Disrupts ion gradients across membranes, affecting the transport of critical molecules in and out of the cell.
   • Examples:
     
     • Daptomycin

This note format highlights the essential information concisely while maintaining clarity. Let me know if you’d like more details on any part!

Question 5

What do Beta-lactams function?

What does this lead to?

Tyoe of anitbiotic

Answer 5

• 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

Question 6

6)	How do the following antibiotic function in the bacterial cell:
•	Cyloserine
•	Bacitracin
•	Vancomycin
•	Β-lactams

Answer 6

• Cyloserine functions inside the bacterial cells
• Bacitracin functions in the cell membrane
• Vancomycin and Beta-lactams function outside the cell on the cell wall

Question 7

What are the 4 different kinds of penicllin?

1. pen
2. pen
3. di
4. clo
5. met
6. na
7. ox
8. am
9. amo

az
car
po
ti

What are the examples in each section?

Answer 7

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

Question 8

Where do cephalosporins come from?

How do they function?

How are they classified?

How can they be termed?

Answer 8

• 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

Question 9

How do bacterial folate antagonists work?

How is this a good example of selective toxicity?

What are examples of Bacterial folate antagonists?
=> dihydropteroate synthase
=> dihydrofolate reductase
sultry

Are they bacteriostatic or bactericidal

Answer 9

• 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

The explanation you provided outlines how certain antibiotics, specifically bacterial folate antagonists, work by interfering with the folate pathway in bacteria. Let me break it down further:

Folate and Its Role in Cell Metabolism:
- Folate (also known as vitamin B9) is a crucial molecule in cell metabolism. It is involved in processes like DNA synthesis and cell division, particularly by helping to make nucleotides, the building blocks of DNA.
- Humans and other higher organisms do not produce folate themselves. Instead, we obtain it from our diet (e.g., leafy greens, fortified foods). Our cells can use folate directly for these processes.
- Bacteria, however, do produce their own folate through a biosynthesis pathway. This pathway is essential for their growth and reproduction.

How Bacterial Folate Antagonists Work:
- Sulfonamides and Trimethoprim are two types of antibiotics that target bacterial folate metabolism.
- Sulfonamides work by inhibiting an enzyme called dihydropteroate synthase, which is involved in the production of folic acid in bacteria.
- Trimethoprim inhibits another enzyme called dihydrofolate reductase, which further disrupts the folate pathway.

Together, these drugs interfere with the bacterial ability to make folate, and without folate, bacteria cannot properly synthesize DNA or divide. This essentially halts their growth.

Why These Antibiotics Are Safe for Humans:
- Since humans do not produce folate (we get it from our diet), we do not rely on the bacterial folate synthesis pathway. Thus, these antibiotics are selective: they primarily affect the bacteria that are trying to make their own folate, while our own cells (which already have folate available from our diet) are largely unaffected.

Bacteriostatic vs. Bactericidal:
- Bacteriostatic antibiotics (like sulfonamides and trimethoprim) do not kill bacteria directly but instead prevent bacterial growth and reproduction. By stopping bacteria from replicating (because they can’t make the DNA they need), these drugs allow the body’s immune system to clear the infection over time.

• Bactericidal antibiotics, on the other hand, directly kill bacteria. Bacteriostatic drugs don’t kill the bacteria outright but stop them from multiplying, so they are effective at preventing the infection from spreading.

Summary:
- Folate antagonists like sulfonamides and trimethoprim interfere with the folate pathway in bacteria, preventing them from making DNA and growing.
- These antibiotics are safe for humans because we don’t rely on the bacterial folate pathway and obtain folate from our diet.
- They are bacteriostatic, meaning they stop bacterial growth, rather than killing the bacteria directly, allowing the body’s immune system to take over.

Question 10

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?

strekanegen

What type of anti-biotics are these?

Answer 10

Here’s the information rewritten and organized for clarity:

Aminoglycosides: Mechanism of Action and Key Details

Mechanism of Action:
1. Initial Binding:
- Aminoglycosides form ionic bonds with the bacterial cell surface.
- They penetrate the bacterial cell wall by being actively transported across the cell membrane.

2. Cytoplasmic Action:
   
   • Once inside the cytoplasm, aminoglycosides bind to bacterial ribosomes.
   • Binding occurs irreversibly at the interface between the assembled 30S and 50S ribosomal subunits.
3. Effects on Protein Synthesis:
   
   • Prevention of tRNA Binding:
     
     • Aminoglycosides block the binding of tRNA to the 30S ribosomal subunit.
     • Without tRNA, protein synthesis cannot start because amino acids cannot be delivered.
   • mRNA Misreading:
     
     • Aminoglycosides cause misreading of mRNA, leading to the production of defective proteins.
   • They may also bind directly to individual ribosomal subunits to disrupt function.
4. Outcome:
   
   • By inhibiting protein synthesis, aminoglycosides prevent essential bacterial functions.
   • They are bactericidal (cause bacterial cell death).

Examples of Aminoglycosides:
1. Streptomycin
2. Kanamycin
3. Neomycin
4. Gentamicin

This explanation is streamlined and emphasizes the step-by-step mechanism and clinical relevance.

Question 11

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?

Answer 11

• 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

Question 12

What is unique about Chloramphenicol?

What do Chloramphenicol, erythromycin and Clindamycin do?

How do they do this?

What is the additional function of erythromycin?

Answer 12

• 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

Question 13

Here are four questions, one for each section:

1. Key Characteristics: What are the types of fluoroquinolones?
2. Mechanism of Action: what does it do?
3. What two factors are used to define fluoroquinolones?
4. Limitations and Side Effects: what are the side effects of the broad-spectrum activity of fluoroquinolones ?

Answer 13

Here’s a clearer and more structured version of the information about fluoroquinolones:

Fluoroquinolones: Overview and Mechanism of Action

Key Characteristics:
- Fluoroquinolones are synthetic antibiotics.
- They are classified based on their spectrum of activity:
1. Broad-Spectrum Agents (effective against many bacterial types):
- Ciprofloxacin
- Ofloxacin
- Norfloxacin
2. Narrow-Spectrum Agent:
- Nalidixic acid (not fluorinated).

Mechanism of Action:
1. Target Enzyme:
- Fluoroquinolones inhibit bacterial DNA gyrase, an enzyme crucial for:
- Introducing negative supercoils in DNA.
- Allowing proper transcription and DNA replication.

2. DNA Folding and Supercoiling:
   
   • DNA needs to be folded to be read and supercoiled to be stored efficiently.
   • Fluoroquinolones prevent these processes by disabling DNA gyrase, leading to:
     
     • DNA that cannot be properly folded, so transcription (gene reading) is blocked.
     • Improperly stored DNA interfering with cellular function.
   • As a result, bacterial cells cannot function or reproduce, leading to cell death.

Pharmacokinetics:
- Fluoroquinolones are studied for their:
1. Spectrum of Activity: Which organisms the drug can kill.
2. Pharmacokinetics: The study of how the drug is absorbed, distributed, and excreted over time.

Limitations and Side Effects:
- Their broad-spectrum activity means they can disrupt normal microbiota in the body, leading to:
- Imbalances in healthy bacteria.
- Potential side effects from affecting non-target microorganisms.

This revised explanation highlights the mechanism, classification, and limitations in an organized and easy-to-follow manner.