31. Antibiotics and anti-fungals

Question 1

outline the key features of bacteria

Answer 1

• single-cell microorganisms
• they have a cell wall and cell membrane
• they have an entire phylogenetic domain
• 1/3 are pathogenic

Question 2

describe the key features of gram + bacteria and give an example

Answer 2

prominent, thick peptidoglycan cell wall

e.g. staphylococcus aureus

Question 3

describe the key features of gram - bacteria and give an example

Answer 3

outer membrane with lipopolysaccharide

e.g. E-coli

Question 4

describe the key features of mycolic bacteria and give an example

Answer 4

outer mycolic acid layer

e.g. mycobacterium tuberculosis

Question 5

how is an important protein in prokaryotic nucleic acid synthesis made?

Answer 5

dihydropteroate (DHOp) is produced from paraaminobenzoate (PABA) by DHOp synthase and converted into dihydrofolate (DHF). DHF reductase then converts DHF into tetrahydrofolate (THF) which is important in DNA synthesis

Question 6

what important protein is involved in prokaryotic DNA replication?

Answer 6

DNA gyrase (topoisomerase) releases tension from the DNA molecules, allowing DNA replication to occur

Question 7

what important protein is involved in prokaryotic RNA synthesis?

Answer 7

RNA polymerase produces RNA from a DNA template

Question 8

what important structures are involved in prokaryotic protein synthesis?

Answer 8

ribosomes

RNA molecules go through prokaryotic ribosomes which produce protein from RNA templates

Question 9

what prevents dihydropteroate (DHOp) from being made? how successful is it?

Answer 9

sulphonamides inhibit DHOp synthase

the vast majority of bacteria are resistant to sulphonamides

Question 10

what prevents tetrahydrofolate (THF) from being made?

Answer 10

trimethoprim inhibits DHF reductase

Question 11

what interferes with DNA replication?

Answer 11

fluoroquinolones inhibit DNA gyrase and topoisomerase IV

Question 12

what inhibits RNA polymerase? what does this result in?

Answer 12

rifamycins

bacterial death because there is reduced production of proteins required for bacterial cell survival

Question 13

what are bacterial ribosomes inhibited by?

Answer 13

• aminoglycosides (e.g. gentamicin)
• chloramphenicol
• macrolides (e.g. erythromycin)
• tetracyclines

Question 14

what type of bacteria are most susceptible to drugs and why?

Answer 14

gram - bacteria because they don’t have a prominent cell wall like gram + bacteria

Question 15

what occurs in step 1 of bacterial wall synthesis - peptidoglycan synthesis?

Answer 15

• a pentapeptide is created on N-acetyl muramic acid (NAM)

- N-acetyl glucosamine (NAG) associates with NAM forming peptidoglycan

Question 16

what occurs in step 2 of bacterial wall synthesis - peptidoglycan transportation?

Answer 16

• peptidoglycan is transported across the cell membrane by a bactoprenol molecule
• once it is in the periplasm, it undergoes a few steps before being incorporated into the bacterial wall

Question 17

what occurs in step 3 of bacterial wall synthesis - peptidoglycan incorporation?

Answer 17

• it is incorporated into the cell wall

- transpeptidase enzyme cross-links peptidoglycan pentapeptides

Question 18

what inhibits peptidoglycan synthesis?

Answer 18

glycopeptides (e.g. vancomycin) which bind the pentapeptides and prevent synthesis

Question 19

what inhibits peptidoglycan transportation?

Answer 19

bacitracin inhibits bactoprenol regeneration

Question 20

what inhibits peptidoglycan incorporation?

Answer 20

b-lactams (e.g. carbapenems, cephalosporins, penicillins) bind covalently to transpeptidase, inhibiting peptidoglycan incorporation into cell wall

Question 21

what inhibits cell wall stability in gram + and gram - bacteria?

Answer 21

lipopeptides (e.g. daptomycin) disrupt gram-positive walls

polymyxins bind to lipolysaccharides (LPS) and disrupt gram-negative cell membranes

Question 22

what are the causes of antibiotic resistance?

Answer 22

• unnecessary and inappropriate prescription
• livestock farming
• lack of regulation (available OTC in some countries)
• lack of development (in recent years)

Question 23

what are beta-lactamases and what do they do?

Answer 23

they are destruction enzymes produced by bacteria

they hydrolyse the C-N bond of the beta-lactam ring in beta-lactam antibiotics

Question 24

what types of antibiotics are more effective in gram + bacteria?

Answer 24

penicillins G and V

Question 25

name 2 b-lactamase resistant antibiotics

Answer 25

flucloxacillin and temocillin

Question 26

what does amoxicillin do?

Answer 26

it has broad spectrum activity but is not b-lactamase resistant

• it has gram - activity
• it is coadministered with clavulanic acid which has b-lactamase resistance

Question 27

how do bacteria resist antibiotics by producing additional targets? give an example

Answer 27

they introduce an additional target that is unaffected by the drug

e.g. E Coli produces a different DHF reductase enzyme, which is resistant to trimethroprim

Question 28

how do bacteria resist antibiotics by altering their target enzymes? give an example

Answer 28

the alter the enzyme that is targeted by the drug so that the enzyme is still effective but the drug is now ineffective

e.g. S Aureus has mutations in the ParC region of topoisomerase IV which gives it resistance to quinolones

Question 29

how do bacteria resist antibiotics by hyper-production? give an example

Answer 29

bacteria significantly increase levels of DHF reductase

e.g. E Coli produces additional DHF reductase enzymes making trimethoprim less effective - the antibiotic is overwhelmed

Question 30

how do bacteria resist antibiotics by altering drug permeation?

Answer 30

they reduce the number of aquaporins and increase efflux systems

this reduces methods of influx and increases methods of efflux to limit drug interaction and is mostly done in gram - bacteria

Question 31

what does the fungal cell membrane contain?

Answer 31

ergosterol

Question 32

what can fungal infections be classified into?

Answer 32

• superficial: outermost layers of skin
• dermatophyte: skin, hair or nails
• subcutaneous: innermost skin layers
• systemic: primarily respiratory tract

Question 33

what are the 2 most common categories of anti-fungal drugs? give an example of each

Answer 33

1. azoles e.g. fluconazole

2. polyenes e.g. amphotericin

Question 34

what do azoles do?

Answer 34

inhibit cytochrome P450-dependent enzymes involved in membrane sterol synthesis (preventing ergosterol production)

fluconazole is used to treat candidiasis and systemic infections

Question 35

what do polyenes do?

Answer 35

punch holes into the cell membrane of fungal cells by interacting with cell membrane sterols to form membrane channels –> cells burst

amphotericin is used to treat systemic infections

Question 36

what is a negative side effect of treatment using amphotericin?

Answer 36

it punches halls into the cell membranes of ALL cells which is bad (but still is more selective for fungal cells)