MSOP1016: Science of Medicines 3 Antibacterial Agents b-lactam antibiotics (Part 3)
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Questions and Answers

What is the key intermediate for semi-synthetic protocols in the synthesis of cephalosporins?

  • Cephalosporin C
  • 6-APA
  • 7-ACA (correct)
  • Penicillin G

    • Which of the following aims is NOT associated with modifications of the chemical structure of cephalosporins?

  • Broaden the antibacterial spectrum
  • Improve acid stability
  • Decrease the activity (correct)
  • Increase the affinity to the receptors (PBPs)

    • What is the mechanism of action of cephalosporins on bacterial cells?

  • Inhibition of bacterial RNA transcription
  • Inhibition of bacterial protein synthesis
  • Inhibition of bacterial DNA replication
  • Inhibition of the transpeptidase enzyme (correct)

    • Which of the following statements is true regarding the structure of cephalosporins compared to penicillins?

    <p>Cephalosporins have a 6-membered dihydrothiazine ring</p> Signup and view all the answers

    Which of the following is a reason for the limited opportunity for modification in cephalosporins?

    <p>Presence of a fused ring system</p> Signup and view all the answers

    Which of the following is NOT a reason for making modifications to the chemical structure of cephalosporins?

    <p>Decrease the activity</p> Signup and view all the answers

    Which modification enhances outer membrane penetration in third generation cephalosporins?

    <p>Aminothiazole ring</p> Signup and view all the answers

    Which of the following best describes the relationship between substituents at position 3 and pharmacokinetics?

    <p>Substituents at position 3 significantly alter pharmacokinetics</p> Signup and view all the answers

    Which of the following best describes the stability of first generation cephalosporins compared to penicillins?

    <p>First generation cephalosporins are more stable than penicillins</p> Signup and view all the answers

    Which of the following best describes the role of oximino groups in cephalosporins?

    <p>Oximino groups increase the potency and spectrum of activity</p> Signup and view all the answers

    Which of the following is a significant factor in the activity of each type of cephalosporin?

    <p>All of the above</p> Signup and view all the answers

    Which of the following is a characteristic of fifth generation cephalosporins?

    <p>All of the above</p> Signup and view all the answers

    Which of the following best describes the relationship between metabolic deacetylation and activity in cephalosporins?

    <p>Metabolic deacetylation decreases activity</p> Signup and view all the answers

    Which of the following best describes the role of EWGs at the acyl side chain in cephalosporins?

    <p>EWGs at the acyl side chain decrease activity</p> Signup and view all the answers

    Which of the following is a characteristic of cephamycins?

    <p>All of the above</p> Signup and view all the answers

    Which of the following best describes the relationship between the acetoxy group and the mechanism of action in cephalosporins?

    <p>The acetoxy group is essential to the mechanism of action</p> Signup and view all the answers

    Study Notes

    Cephalosporins: Classification

    • Around 50 cephalosporins are in clinical use
    • Classification into generations is based on:
      • Spectrum of anti-bacterial activity
      • Chemical sophistication
      • Chronology

    First Generation Cephalosporins

    • Cephalothin was one of the most commonly used
    • Importance of acetoxy group in the mechanism of action
    • Note: acid and alcohol can react to give a lactone
    • Cephaloridine:
      • Esterase stable pyridinium group
      • Exists as a zwitterion, but poorly absorbed

    Improvements in First Generation

    • Improve stability: EWGs at carbon a to side chain amide
    • Improve oral absorption: methyl group at position-3

    Second Generation Cephalosporins

    • Cephamycins: methoxy group at position-7
    • Cefoxitin has a broader spectrum of activity compared to 1st generation
    • Oximinocephalosporins: modification a to side chain amide increases stability against β-lactamases

    Third Generation Cephalosporins

    • Aminothiazole ring enhances outer membrane penetration (Gram-negative)
    • Substituent at position 3 varies pharmacokinetics
    • Major role due to activity against Gram-negative bacteria

    Fourth Generation Cephalosporins

    • Still oximinocephalosporins, but are zwitterionic
    • Dramatically improves outer membrane penetration
    • Good affinity for transpeptidase, low for a variety of β-lactamases

    Fifth Generation Cephalosporins

    • Approved in 2014
    • Urea Pyrazole ring
    • Ceftolozane
    • Effective against MRSA, MDRSP, and P. aeruginosa

    Resistance and Activity

    • Activity of each type of cephalosporin depends on:
      • Ability to reach the bacterial transpeptidase
      • Stability to β-lactamases present
      • Affinity for the target enzyme
    • Example: Cephalosporins and MRSA

    Cephalosporins: Summary

    • Strained β-lactam ring fused to dihydrothiazine ring
    • 1st generation vs penicillins:
      • Better stability against acid and β-lactamases
      • Poor oral availability and lower activity
    • Variation at 7-acylamino side chain alters activity
    • Variation at position 3 alters pharmacokinetics/metabolism
    • Methoxy groups can be added at C-7
    • Synthesis: semi-synthetic procedures from 7-ACA
    • 7-ACA obtained by chemical hydrolysis of cephalosporins requires prior activation of the side chain

    Other β-Lactam Antibiotics

    • Carbapenems: potent, very broad range of activity, low toxicity, and highly resistant to β-lactamases
    • Example: Thienamycin (1976)
    • Monobactams: isolated from natural sources, surprising structures

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    Description

    Explore the lecture outline on Cephalosporins and other b-lactam antibiotics. Learn about the discovery, structure, activity relationships, synthesis, generations, resistance, and comparisons with penicillins. Dive into the potency, activity spectrum, and advantages of Cephalosporins.

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