Intro to Antimicrobial Chemotherapy

Question 1

What is chemotherapy?

Answer 1

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

+ Antibiotics and anti-bacterials can be used interchangeably

Question 2

What are features of Salvarsan?

Answer 2

+ Kills trypanosomes

+ Trypanosomes can become resistant (trypanosomes resistant to one agent remain susceptible to others)

Question 3

What is prontosil?

Answer 3

+ A red dye that inbibits bacteria (antibacterial)

+ Metabolises sulphanilamide: not a dye but still reactive to bacteria

Question 4

How was streptomycin discovered?

Answer 4

+ Antibiotic discovery based on theory that soil organisms may have produced agents to kill mycobacteria derived from soil organisms

+ Soil screened for presence of factors that inhibit mycobacteria

+ Mycobacteria discovered

Question 5

What is selective toxicity?

Answer 5

Central to the use of chemotherapeutic agents:

• when drugs intended to be toxic to the invading organism/cancerous cells but be relatively harmless to the host/normal cells

Question 6

What does the approach of using drugs with selective toxicity depend upon?

Answer 6

The existence of biochemical differences between the target group of cells and the host

Question 7

What are examples of different selective toxicity?

Answer 7

+ Penicillins: in the absence of allergy have very low toxicity and high doses can be used

+ Aminoglycosides have a narrow THERAPEUTIC INDEX thus the dose that causes toxicity is very close to the therapeutic dose

+ For anti-tuberculosis drugs such as isoniazid and pyrazinamide a number of patients will develop hepatotoxicity that is not dose related and may require treatment to be stopped

Question 8

What are the main classes of anti-microbial agents?

Answer 8

+ Beta-lactam and cephalosporin

+ Glycopeptide

+ Cyclicpeptide

+ Phosphonic acids

+ Lipopeptides

Question 9

What are the main mechanisms of action of beta-lactam and cephalosporin?

Answer 9

Preventing peptidoglycan cross-linking

Question 10

What is the target of beta-lactam and cephalosporin?

Answer 10

Penicillin bindng proteins

Question 11

What are examples of beta-lactams and cephalosporins?

Answer 11

+ Penicillin G
+ Flucloxavillin
+ Tazobactam

Question 12

What is the main mechanism of action of glycopeptides?

Answer 12

Prevents transglycolation and transpeptidation

Question 13

What is the target of glycopeptides?

Answer 13

C-terminal D-Ala-D-Ala

Question 14

What are examples of glycopeptides?

Answer 14

+ Vancomycin

+ Teicoplanin

Question 15

What is the main mechanism of action of cyclic peptides?

Answer 15

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

Question 16

What is the target of cyclic peptides?

Answer 16

C55-isoprenyl pyrophosphate

Question 17

What are examples of cyclic peptides?

Answer 17

+ Bacitracin

+ Polymyxin

Question 18

What is the main mechanism of action of phosphonic acids?

Answer 18

Inhibits first stage of peptidolycan synthesis

Question 19

What is the target of phonphonic acids?

Answer 19

murA protein

Question 20

What is an example of a phosphonic acid?

Answer 20

Fosphomycin

Question 21

What is the main mechanism of action of lipopeptides?

Answer 21

Calcium-dependent membrane depolarisation

Question 22

What is an example of a lipopeptide?

Answer 22

Daptomycin

Question 23

What are the different classes of penicillins?

Answer 23

1. Penicillins G and V
2. β-lactamase-resistant penicillins
   - cloxacillin, oxacillin, nafcillin, dicloxacillin, methicillin
3. Broad-spectrum penicillins
   - ampicillin
   - amoxicillin
4. Extended spectrum penicillins
   - carbenicillin
   - ticaracillin
   - azlocillin
   - piperacillin

Question 24

How are cephalosporins classified?

Answer 24

By generations in the order in which they were developed:
- 1st, 2nd, 3rd

Now can be termed by means of administration:

• oral (cephalexin)
• parenteral (cefuroxime, cefotaxime)

Question 25

What are bacterial folate antagonists?

Answer 25

Sulphonamides & trimethoprim:

• antibiotics which act through an inhibition of the folate pathway in bacteria
• humans don’t have folate (get it via diet)
• this makes bacteria susceptinble to drugs which interfere with folate metabolism: selective toxicity target

Question 26

What is the role of amino glycosides work?

Answer 26

INHIBIT PROTEIN SYNTHESIS

1. Form ionic bonds at cell surface
2. Penetrate cell wall via a transport mechanism across cell membrane
3. Diffuse into cytoplasm then bind to bacterial ribosomes

Question 27

What occurs during the inhibition of protein synthesis by aminoglycosides?

Answer 27

1. Bind to ribosomes
   (i) at interface between assembled 30S and 50S units
   (ii) directly to individual subunits
2. Inhibits protein synthesis by misreading mRNA

Question 28

What are examples of aminoglycosides?

Answer 28

+ Streptomycin
+ Kanamycin
+ Neomycon
+ Gentamycin

Question 29

What are features of tetracyclines?

Answer 29

1. They prevent attachment of tRNA to acceptor site on mRNA-ribosomal complex
2. This prevents addition of amino acids to peptide chain
3. Weakly bound to ribosomes, unlike aminoglycosides
4. Differences in activity of individual tetracyclines related to solubility in bacteria lipid membrane

Question 30

What is the role of chloramphenicol, erythromycin and clindamycin?

Answer 30

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

+ This prevents association of peptidyl-transferase with amino acid and no peptide bond formed i.e no transpepidation

+ May also prevent translocation of ribosome down mRNA template (erythromycin)

Question 31

What are fluoroquinolones?

Answer 31

Synthetic antibiotics

Question 32

What are the classes of fluoroquinolones?

Answer 32

1. Broad spectrum:
   - ciprofloxacin, ofloxacin, norfloxacin
2. Narrower-speectrum
   - Cinoxacin, nalidixic acid

Question 33

How do fluoroquinolones work?

Answer 33

+ Act by inhibiting bacterial Topoisomerase II (DNA gyrase)

+ This enzyme catalyses introductionof negative supercoil in DNA permitting transcription and replication