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Medicine Year 1 Semester 1 - Part 2 > Principles of Antimicrobial Chemotherapy > Flashcards

Principles of Antimicrobial Chemotherapy Flashcards

1
Q

Chemotherapy

A

Applied to the use of chemicals (either natural or synthetic) to inhibit the growth/replication of ‘invading organisms’ or cancerous cells within the body.

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2
Q

Erhlichs discoveries

A

Discovered and established the concept of selective toxicity.

  • Gram staining technique
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3
Q

Erhlichs discovery about trypanosomes

A

Trypanosomes were killed by Salvarsan

Trypanosomes could become resistant

Trypanosomes resistant to one agent, remained susceptible to others.

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4
Q

Domagk and rational development of antibiotics

A

He pursued a series of dyes as potential antibacterials.

Discovered PRONTOSIL : a red dye that inhibited bacteria

Jacques and Therese Trefouel found that prontosil was metabolised to sulphanilamide which was not a dye, but still active against bacteria.

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5
Q

Domagk’s achievement

A

He developed the concept of rational design of anti-bacterials.

He went on to develop anti-tuberculosis agents.

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6
Q

Penicillin

A

Was a chance discovery by Alexander Fleming.

He was unable to make enough material to make treatment possible.

So, he published the discovery as a method to select bacteria on agar.

He was aware of the potential threat of AMR.

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7
Q

Florey and Chain

A

Recognised the value of penicillin as potential treatment of bacterial infection.

Used large fermenters to create enough starting material to allow extraction of penicillin.

They worked in great secrecy during the war, later in America.

The urine of treated patients was collected and penicillin re-extracted.

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8
Q

Penicillin G

A

Semi-synthetic

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9
Q

Penicillin nucleus

A

Doesn’t exist in nature

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10
Q

Ampicillin

A

Semi-synthetic

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11
Q

Pre-1946 treatments

A

Pelargonium roots
Cod liver oil
Gold

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12
Q

Waksman and Schatz

A

Antibiotic discovery based on a theory that soil organisms may have produced agents to kill mycobacteria which were derived from soil organisms.

Thousands of soil samples were screened for the presence of factors that inhibit mycobacteria.

Streptomycin discovered.

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13
Q

Streptomycin

A

Single most effective drug against TB

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14
Q

The streptomycin trial

A

Treatment groups :

  • Bed rest : 52 patients
  • Streptomycin : 55 patients
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15
Q

The streptomycin trial short term results of deaths assessed

A

6 months

Bed rest : 27%
Streptomycin : 7%

P = 0.01

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16
Q

The streptomycin trial long term results of deaths assessed

A

5 years

Bed rest : 62%
Streptomycin : 58%

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17
Q

How many of the streptomycin patients that were tested have developed resistance ?

A

35 out of 41

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18
Q

Describe how antibiotics can be developed

A

Based on a theory of activity - even though it is subsequently proved to be false

As a result of chance occurrences

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19
Q

Describe how antibiotics can be discovered

A

On the basis of systematic screening of natural products.

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20
Q

Selective toxicity

A

Reduces damage to the host/normal cells [PATIENT]

Maximises damage to invading organism / cancerous cells.

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21
Q

Principles of selective toxicity

A
  1. Central to the use of chemotherapeutic agents is
    the concept of SELECTIVE TOXICITY. These drugs are
    intended to be toxic to the invading organism or
    cancerous cell but be relatively harmless to the host
    or normal cells.
  2. This approach depends upon the existence of
    biochemical differences between the target group of
    cells and the host.
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22
Q

Chemotherapeutic agents

A

These drugs are intended to be toxic to the invading organism or cancerous cell but be relatively harmless to the host or normal cells.

23
Q

Examples of different selective toxicity

A

Penicillins
Amino glycosides

24
Q

Penicillins (example of selective toxicity)

A

In the absence of allergy, they have a very low toxicity and high doses can be used.

25
Q

Amino-glycosides (example of selective toxicity)

A

They have a narrow therapeutic index thus the dose that causes toxicity is very close to the therapeutic dose.

26
Q

Therapeutic index

A

Lethal dose 50% / Effective dose 50%

27
Q

Anti-tuberculosis drugs

A

Isoniazid and Pyrazinamide

A number of patients will develop hepatoxicity that is not dose related and may require treatment to be stopped.

28
Q

Main mechanisms of action of the main antibiotic classes

A

Class 1-3 reactions

29
Q

Class 1 reactions

A

Result in the synthesis of the precursor molecules necessary for Class 2 reactions.

Precursor molecules = NH4+ and SO4 2-

30
Q

Class 2 reactions

A

Result in the synthesis of the constituent molecules.

Constituent molecules :

  • Hexosamines
  • Amino acids
  • Nucleotides
31
Q

Class 3 reactions

A

Constituent molecules are then assembled into macromolecules.

  • Peptidoglycan
  • Proteins
  • RNA
  • DNA
32
Q

Function of pepidoglycans

A

They make up the cell wall of bacteria and do not occur in eukaryotes.

The cell wall is made up from various numbers of strands of pepitdoglycans.

33
Q

Structure of peptidoclycans

A

The strands of peptidoglycan are made up of multiples of amino-acids; N-acetylglucosamine and N-acetylmuramic acid dimers.

The n-acetylmuramic acid has a short peptide side chain (hence peptidoglycan)

The peptide side chains are cross linked to form a latticework.

Cross linking gives the cell all its strength.

34
Q

Beta-lactam
Cephalosporin

A

TARGET : Penicillin binding proteins

MECHANISMS : Preventing peptidoglycan cross-linking

EXAMPLES: Penicillin G, Flucloxacillin, Cefoxatin

35
Q

Glycopeptide

A

TARGET : C-terminal D-Ala-D-Ala

MECHANISMS : Prevents transglycolation and transpeptidation

EXAMPLES : Vancomycin, Teicoplanin

36
Q

Cyclic peptide

A

TARGET : C55-isopropyl pyrophosphate

MECHANISMS : Prevents carriage of building-blocks of peptidoglycan bacterial cell wall outside of the inner membrane.

EXAMPLES : Bacitracin, Polymyxin

37
Q

Phosphonic acids

A

TARGET : murA protein

MECHANISMS : Inhibits first stage of peptidoglycan synthesis

EXAMPLES : Fosphomycin

38
Q

Lipopeptides

A

TARGET : Cell wall stress simulation

MECHANISMS : Calcium-dependent membrane depolarisation

EXAMPLES : Daptomycin

39
Q

Function of beta lactams

A

Prevent the cross-linking peptides from binding to the tetra-pepide side chains.

40
Q

Name some penicillins

A

Penicillins G and V
Beta-Lactamase-resistant penicillins

Broad spectrum penicillins
Extended spectrum penicillins

41
Q

Beta-Lactamase-resistant penicillins

A

Methicillin
Oxacillin
Nafcillin
Cloxacillin
Dicloxacillin

42
Q

Broad spectrum penicillin

A

Ampicillin
Amoxicillin

43
Q

Extended spectrum penicillins

A

Carbenicillin
Ticaracillin
Azlocillin
Piperacillin

44
Q

Cephalosporins

A
  1. Come from the fungus Cephalosporium Acremonium.
  2. Work by the same mechanisms as penicillins
  3. Classified by generations in the order in which they
    were developed.
  • 1st, 2nd and 3rd generation.
  1. Now can be termed by means of administration; Oral is Cephalexin, Parenteral are Cefuroxime & Cefotaxime
45
Q

Bacterial Folate agonists

A
  1. SULPHONAMIDES & TRIMETHOPRIM
    These are antibiotics which act through an inhibition of the folate pathway in bacteria.
  2. Folate system important in cell metabolism
  3. Bacteria must make their own supply but we don’t as we get it in diet.
  4. This makes bacteria susceptible to drugs which interfere with folate metabolism: thus we have our ‘selective toxicity’ target.
  5. Sulphonamides mark the beginning of antimicrobial
    chemotherapy dating back to the 1930s and preceding the penicillins.
46
Q

Aminoglycosides

A
  1. Form Ionic bonds at the cell surface
  2. Penetrate the cell wall by a transport mechanism across the cell membrane.
  3. Diffuse into the cytoplasm and then binds to the bacterial ribosomes.
47
Q

Examples of amino glycosides

A

Streptomycin
Kanamycin
Neomycin
Gentamicin

48
Q

Inhibition of protein synthesis

A

Genetamcin :

  1. Binds to the ribosomes :

i. At the interface between the assembled 30s and 50s subunits.
ii. Directly to the individual subunits.

  1. Inhibits protein synthesis by misreading of mRNA.
49
Q

Tetracyclines

A
  1. They prevent attachment of the tRNA to the acceptor (A) site on the mRNA-ribosomal complex.
  2. This prevents the addition of amino acids to the peptide chain.
  3. Unlike the aminoglycosides, they are only weakly bound to the ribosomes.
  4. Differences in the activity of individual tetracyclines are related to their solubility in the lipid membrane of the bacteria.
50
Q

Chloramphenicol, Erythromycin and Clindamycin

A

Prevent the addition of new amino acids to the growing peptide chain by binding to the ribosomes.

This prevents association of the peptidyl-transferase with the amino acid and no peptide bond is formed
i.e. no transpeptidation.

May also prevent translocation of the ribosome down the mRNA template (Erythromycin).

51
Q

Fluoroquinolones

A

Fully synthetic antibiotics

52
Q

Main classes of antibacterial agents - fluoroquinolones

A

Broad-spectrum agents

  • Ciprofloxacin
  • Ofloxacin
  • Norfloxacin

Narrower spectrum agents

  • Nalidixic acid (first introduced and is not fluorinated)
53
Q

Describe the action of nalidixic acid

A
  1. Act by inhibiting bacterial DNA Topoisomerase II also known as DNA gyrase.
  2. This enzyme catalyses the introduction of negative supercoil in DNA permitting transcription and replication.
54
Q

Use of fluoroquinolone

A

Defined by spectrum of activity
Defined by pharmacokinetics

Often limited by impact on other flora

Medicine Year 1 Semester 1 - Part 2 (37 decks)

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