4.8 Antimicrobial agents

Question 1

What are the different types of antimicrobial agents?

Answer 1

• naturally occurring antibiotics, metabolic product of microbes that kill or inhibit other organisms
• Chemotherapeutic agents which are synthetic
• Semi-synthetic agents which may be antibiotics from natural sources but have been chemically modified to make them more stable or reduce toxicity
• Selective toxicity

Question 2

What are the four categories by which you classify antibiotics?

Answer 2

• Source
• Broad mechanism of action
  
  • Bactericidal vs bacteriostatic
  • Target
• Spectrum
  
  • Narrow or broad
• Chemical structure

Question 3

How does this show difference between bacteriostatic and bactericidal organisms?

Answer 3

• Bacteriostatic allows immune system to cope
• Bactericidal actively killing the bacteria sharp decrease in number of bacteria
• Immunocompromised them always use bactericidal so no chance of infection coming back

Question 4

What are three things you should consider when making antimicrobial drugs?

Answer 4

1. Selective toxicity

• You want to target the organism but not the humans so find differences in the structure and metabolism of the bacterium and host cells
• Antimicrobial agent should act at a target site present in infecting agent but not the host cell

2. Access to the site of infection
3. Provision of appropriate levels for an appropriate time
   * Maintain adequate levels to allow inhibition or killing

Question 5

What are the targets on microbes of antimicrobial agents?

Answer 5

Question 6

Answer 6

• Not active against bacteria that invade into cell and survive inside them
• Not active againt species that lack cell wall or impenetrable wall like tuberculosis

Question 7

What is the structure of peptidoglycan?

Answer 7

Building blocks contain small penta peptide linked together through pentaglycine bridge

Question 8

How do beta lactams target crosslinking of peptidoglycan?

Answer 8

• Linked through glycine bridges by transpeptidases
• Beta lactams bind to transpeptidases and interfere with building up and formation of layer of peptidoglycan

Question 9

What structure does Penicillin G have similairity to?

Answer 9

Question 10

How does Vancomycin attack the crosslinking of peptidoglycan?

Answer 10

• binds to terminal D-ala-D-ala residues thus, prevents incorporation of NAG-NAM subunit into growing peptidoglycan chain
• Vancomycin large molecules difficulty to penetrate into gram negative cells
• Needs to be given by injection gram positive only

Question 11

How can bacteria have resistance to beta lactams?

Answer 11

Beta-lactamase

• expression of beta lactamases by the microorganism
• Enzymes that catalyse hydrolysis of the beta lactam ring

Question 12

Answer 12

• Ring in the antibiotic hydrolysed
• Become inactive cannot bind to transpeptidases anymore
• These genes are widespread, released in the extra cellular environemtn and then picked up
• Secreted by gram positive

Question 13

How do altered penicillin binding proteins give resistance to beta lactam?

Answer 13

• Transpeptidases that link building blocks together, bacteria can express different forms of penicillin binding proteins
• By expressing altered proteins no longer sensitive to action of beta lactams

Question 14

Which antibiotics act on the recognition part of protein synthesis?

Answer 14

aminoglycosides, tetracyclines

Question 15

How do aminoglycosides inhibit the early stages of protein synthesis?

Answer 15

• The association of the mRNA with the 30S ribosome
• Misreading of the mRNA code and interfere with peptide product of protein synthesis
• Act on gram negative generally

Question 16

Are aminoglycosides bacteriocidal or bacteriostatic?

Answer 16

• Bactericidal
• They are quite toxic and might interfere with hearing and toxic to the kidney
• But can use in topical creams

Question 17

Where are aminoglycosides modified?

Answer 17

Question 18

What are the mechanisms of resistance to aminoglycosides?

Answer 18

Question 19

What are the mechanisms of resistance to antimicrobial agents?

Answer 19

Drug inactivation

• By hydrolysis, e.g. β-lactams
• By covalent modification, e.g. aminoglycosides

Altering the target of drug action

• Modify target to a less sensitive form, e.g. β-lactam
• Overproduce target, e.g. vancomycin

Question 20

How is alteration of target achieved in resistance to glycopeptides?

Answer 20

• Mutation of terminal D-ala - D-ala to D-ala-D-lactate in enterococci
• Bacteria become resistant by changing d ala to lactate so vancomycin cannot bind

Question 21

How is production of excess target achieved in resistance to glycopeptides?

Answer 21

• Production of excess target (peptidoglycan) in Staphylocci
• Produce so much of the building blocks that it bind to g ala but there is enough to keep building peptidoglycan layer

Question 22

How is failure to activate inactive precursor of drug a resistance mechanism?

Answer 22

• Metronidazole inactive compounds that need to be cleaved and occur in microorganism but not in our own cells
• Metronidazole inactive compounds that need to be cleaved and occur in microorganism but not in our own cells
• PFOR enzyme needs to be reduced or activated that results in activation after it has entered the microbe

Question 23

What is the intrinsic genetic basis of resistance in microbes?

Answer 23

Intrinsic due to:

• cell wall impermeability (vancomycin and G -ves)
• lack of target (Mycoplasma - no cell wall; enterococci - unable to synthesise folic acid)
• chromosomal resistance gene (Pseudomonas beta-lactamase)

Question 24

What is the acquired genetic basis of resistance?

Answer 24

• mutation
• horizontal gene transfer (e.g. bacteriophages, plasmids)

Question 25

What are the three ways in which bacterial transfer of DNA can occur?

Answer 25

Question 26

What is plasmid mediated conjugation?

Answer 26